INDEX

1. Introduction 1-15

1.1 Pre-diabetes 1
1.2 Diabetes 1
1.3 Etymology 6
1.4 Epidemiology 6
1.5 Insulin and diabetes mellitus 7
1.6 Pathophysiology of diabetes 8
1.7 Signs and Symptoms 9
1.8 History 11

2. Review Articles 16-38

2.1 History 16
2.2 Oral antidiabetic agent (Clinically used) 18
2.3 Oral antidiabetic agent (Clinically not used) 20

3. Classification of Anti-Diabetic Drug 39-40

4. Insulin 41-46

4.1 Discription 42
4.2 Variants of Insulin products 42

5. Secretagogues 47-77

5.1 K+ ATP 47
5.1.1 Sulfonylureas 47
 5.1.2 Meglitinide 60
5.2 GLP-I analogues 63
5.3 Protein Tyrosin Phosphate 1β inhibitors 65
5.4 Dipeptidyl peptidase-4 inhibitors 72

6. Sensitizers 78-89

6.1 Biguanide 78
6.2 Thiazolidinedione 82
6.3 PPAR modulator 87

7. Other Insulin Analogues 90-95

7.1 Animal insulin 90

7.2 Chemically and enzymatically modified insulin 91
7.3 Non hexameric insulin analogues 91
7.4 Shifted isoelectric point insulin 91
7.5 Carcinogenicity 92

8. Other analogues 96-103

8.1 α-Glucosidase inhibitor 96

8.2Amylin 100
8.3 Sodium-glucose transport proteins 102

9. Other Drugs 104

10. Natural antidiabetic agent 106
11. References 107
 LISTS OF FIGURE

No Title Page No

1.1 Normal insulin signaling pathways 8

1.2 Complications of diabetes mellitus 10

4.1 Primary structure of proinsulin, depicting cleavage sites to produce 41

insulin.

4.2 Insulin structure 42

5.1 Classification of PTP 66

5.2 Role of PTP-1β in insulin signaling 67

5.3 Structure of PTP-1β showing main sites 68

5.4 Structure of PTP-1β showing simultaneous dephosphorylation of 69

insulin receptor

5.5 Dipeptidyl peptidase-4 inhibitor 72

6.1 PPAR α and γ pathways. 87

8.1 Amino acid sequence of Amylin with disulfide bridge and cleavage 100
sites of insulin degrading enzyme indicated with arrows
 ANTI-DIABETIC AGENTS

DIABETES
1. INTRODUCTION1-20
1.1 Pre-diabetes

Prediabetes is a stage between normal and diabetes stage. It is an alarming sign for
upcoming diabetes or a chance to change your future. Universally, numerous terms are
given like, Borderline Diabetes, Chemical Diabetes, Touch of Diabetes etc. The term
Prediabetic was given by the US Department of Health And Human Services on 27th
march 2002 with an intention to create awareness and convey seriousness of the condition.
Also, they motivated people to option for appropriate treatment and lifestyle modification.
According to that 17 million US citizens are diabetic and 16 millions are prediabetic. It
defines it as a stage before the development of diabetes, with normal glucose tolerance, but
with an increased risk of developing diabetes in near future.

Prediabetes is a condition when your blood sugar level triggers higher than normal,
but not so high that we can justify it as type 2 diabetes. According to the Centers for
Disease Control and Prevention, 41 million U.S. adults aged 40 to 74 have prediabetes.
And the same reports from, The American Academy of Pediatrics show that, one of every
10 males and one of every 25 females have prediabetes aged from 12 to 19 years.

1.2 Diabetes

Diabetes is a disease in which levels of blood glucose, also called blood sugar, are
above normal. People with diabetes have problems converting food to energy. Normally,
after a meal, the body breaks food down into glucose, which the blood carries to cells
throughout the body. Cells use insulin, a hormone made in the pancreas, to help them
convert blood glucose into energy.

People develop diabetes because the pancreas does not make enough insulin or
because the cells in the muscles, liver and fat do not use insulin properly, or both. As a
result, the amount of glucose in the blood increases while the cells are starved of energy.
Over the years, high blood glucose, also called hyperglycemia, damages nerves and blood

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vessels, which can lead to complications such as heart disease, stroke, kidney disease,
blindness, nerve problems, gum infections, and amputation.
As per global projections by International Diabetes Federation (IDF), the number
of diabetes patients has risen sharply in recent years. While in 1985, 30 million people had
diabetes worldwide; the number rose to 150 million in 2000, 285 million in 2010 and is
estimated to be 435 million - 7.8% of the adult world population by 2030.India has the
highest number of diabetics in the world. By next year, the country will be home to 50.8
million diabetics, making it the world's unchallenged diabetes capital. And the number is
expected to go up to 87 million -8.4% of the country's adult population -- by 2030.
Diabetes mellitus is a common disease in the all over world.The crude prevalence
rate of diabetes in urban areas is about 9% and that the prevalence in rural areas has also
increased to around 3% of the total population. If one takes into consideration that the total
population of India is more than 1000 million then one can understand the sheer numbers
involved. Taking an urban-rural population distribution of 70:30 and an overall crude
prevalence rate of around 4%, at a conservative estimate, India is home to around 40
million diabetics and this number is thought to give India the dubious distinction of being
home to the largest number of diabetics in any one country. Diabetes prevalence has
increased steadily in the last half of this century and will continue rising among U.S.
population. It is believed to be one of the main criterions for deaths in United States, every
year. This diabetes information hub projects on the necessary steps and precautions to
control and eradicate diabetes, completely.
Diabetes is a metabolic disorder where in human body does not produce or
properly uses insulin, a hormone that is required to convert sugar, starches, and other food
into energy. Diabetes mellitus is characterized by constant high levels of blood glucose
(sugar). Human body has to maintain the blood glucose level at a very narrow range,
which is done with insulin and glucagon. The function of glucagon is causing the liver to
release glucose from its cells into the blood, for the production of energy.
There are three main types of diabetes:
 Type 1 diabetes
 Type 2 diabetes
 Gestational diabetes

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1.2.1 Type 1 Diabetes

The insulin-dependent diabetes mellitus (IDDM), normally takes place when the β-
cells of the prevailing pancreatic islets of Langerhans are destroyed, perhaps by an
autoimmune, mechanism, as a consequence of which the ‘insulin production’ in vivo is
overwhelmingly insufficient. Subjects undergoing such abnormalities in biological
functions may show appreciable metabolic irregularity that may ultimately lead to develop
diabetic β-ketoacidosis together with other manifestations of acute diabetes.
Therapeutically Type-I diabetes is largely treated with insulin.

1.2.2 Type 2 Diabetes

The noninsulin-dependent diabetes mellitus (NIDDM), i.e., type 2 diabetes, is
most abundantly linked with obesity in its adult patients largely. In such a situation, the
insulin levels could be either elevated or normal; and therefore, in short, it is nothing but a
disease of abnormal ‘insulin resistance’. However, it has been duly observed that the
impact of the disease is relativel milder, occasionally leaving to β-ketoacidosis and may
also be accompanied by certain other degenerative phenomena in vivo. The etiology of the
condition bears a strong genetic hereditar; and, hence, insulin therapy may not prove to be
quite effective.

1.2.3 Gestational Diabetes

Some women develop gestational diabetes late in pregnancy. Although this form of
diabetes usually disappears after the birth of the baby, women who have had gestational
diabetes have a 40 to 60 percent chance of developing type 2 diabetecs within 5 to 10
years. Maintaining a reasonable body weight and being physically active may help prevent
development of type 2 diabetes.
About 3 to 8 percent of pregnant women in the United States develop gestational
diabetes. As with type 2 diabetes, gestational diabetes occurs more often in some ethnic
groups and among women with a family history of diabetes. Gestational diabetes is caused
by the hormones of pregnancy or a shortage of insulin. Women with gestational diabetes
may not experience any symptoms.
Type 1 and Type 2 diabetes impede a person’s carefree life. When breakdown of
glucose is stopped completely, body uses fat and protein for producing the energy. Due to
this mechanism symptoms like polydipsia, polyuria, polyphegia, and excessive weightloss
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can be observed in a diabetic. Desired blood sugar of human body should be between 70
mg/dl -110 mg/dl at fasting state. If blood sugar is less than 70 mg/dl, it is termed as
hypoglycemia and if more than 110 mg /dl, it’s hyperglycemia.
Diabetes is the primary reason for adult blindness, end-stage renal disease (ESRD),
gangrene and amputations. Overweight, lack of exercise, family history and stress increase
the likelihood of diabetes. When blood sugar level is constantly high it leads to kidney
failure, cardiovascular problems and neuropathy. Patients with diabetes are 4 times more
likely to have coronary heart disease and stroke. Gestational diabetes is more dangerous
for pregnant women and their fetus.

Though, Diabetes mellitus is not completely curable but, it is controllable to a great

extent. So, you need to have thorough diabetes information to manage this it successfully.
The control of diabetes mostly depends on the patient and it is his/her responsibility to take
care of their diet, exercise and medication. Advances in diabetes research have led to
better ways of controlling diabetes and treating its complications.

1.2.4 Other specific types:

1. Genetic defects of beta cell function

 Chromosome 20q, HNF-4α (MODY1)

 Chromosome 7p, glucokinase (MODY2)
 Chromosome 12q, HNF-1α (MODY3)
 Chromosome 13q, insulin promoter factor (MODY4)
 Chromosome 17q, HNF-1β (MODY5)
 Chromosome 2q, neurogenic differentiation1/b-cell ebox
transactivator 2 (MODY6)
 Mitochondrial DNA

2. Genetic defects in insulin action

 Type 1 insulin resistance
 Leprechaunism
 Rabson-mendenhall syndrome
 Lipoatrophic diabetes

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3. Diseases of exocrine pancreas

 Pancriatitis
 Trauma/pancreatectomy
 Neoplasia
 Cystic fibrosis
 Hemochromatosis
 Fibrocalculous pancreatopathy

4. Endocrinopathies
 Acromegaly
 Cushing’s syndrome
 Glucagonoma
 Pheochromocytoma
 Hyperthyroidism
 Somatostatinoma
 Aldosteronoma

5. Drug or chemical induced

 Vacor
 Pentamidine
 Nicotinic acid
 Glucocorticoids
 Thyroid hormone
 Diazooxide
 Β-Adrenergic agonists
 Thiazides
 Dilantin
 Interferon

6. Infections
 Congenital rubella
 Cytomegalovirus

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7. Uncommon forms of immune mediated diabetes

 Stiff-man syndrome
 Klinefelter’s syndrome
 Turner’s syndrome
 Wolfram’s syndrome
 Friedeich’s ataxia
 Huntington’s chorea
 Laurence-Moon-Biedel syndrome
 Porphyria
 Prader-Willi syndrome

1.3 Etymology

The word diabetes was coined by Aretaeus (81–133 CE) of Cappadocia. The word
is taken from Greek diabaínein, and literally means “passing through,” or “siphon”.
"Mellitus" comes from the Greek word "sweet". Apparently, the Greeks named it thus
because the excessive amounts of urine diabetics produce (when blood glucose is too high)
attracted flies and bees because of the glucose content. The ancient Chinese tested for
diabetes by observing whether ants were attracted to a person's urine; medieval European
doctors tested for it by tasting the urine themselves, a scene occasionally depicted in
Gothic reliefs.The word became diabetes from the English adoption of the medieval Latin,
diabetes. In 1675, Thomas Willis added mellitus to the name (Greek mel “honey,” sense
‘honey sweet’) when he noted that a diabetic’s urine and blood has a sweet taste (first
noticed by ancient Indians).

It is probably important to note that passing abnormal amounts of urine is a

symptom shared by several diseases (most commonly of the kidneys), and the single word
diabetes is applied to many of them. The most common of them are diabetes insipidus and
the subject of this article, diabetes mellitus.

1.4 Epidemiology
Diabetes mellitus is a disease that occurs worldwide and the incidence is higher in
relatives of diabetes, people older than 45 years and those who are currently or were obese.
Studies of identical twins show greater than 94% concordance for developing NIDDM.

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Furthermore, there is a high prevalence of NIDDM in offspring’s of parents with the

disease and also in siblings of affected individuals. Persons more than 20 % over ideal
body weight also have a greater risk of developing NIDDM. In addition, previously
identified impaired glucose tolerance, gestational diabetes, hypertension or significant
hyperlipidemias are associated with an increased risk of NIDDM.

1.5 Insulin and diabetes mellitus

Insulin is a 58-kDa polypeptide hormone produced by pancreatic islets of

langerhance regulating, in vivo, the storage, release, and utilization of nutrient energy,
carbohydrate in the form of glucose, fat and protein, in response to the changing supply
and demand.

The major metabolic actions of insulin include:

 Promotion of uptake and storage of glucose in liver and muscle in the form of
glycogen.
 Suppression of hepatic glycogenolysis and gluconeogenesis.
 Increasing the rate of glucose oxidation in muscle.
 Suppression of lipolysis and the release of fatty acid from adipose tissue.
 Enhancing triglyceride synthesis and storage and de novo lipogenesis from
carbohydrate in liver and fat.
 Promotion of amino acid uptake and protein synthesis in muscle.
 Regulation of gene transcription.

Insulin initiates its actions by binding to the cell surface receptors on target cells
(mostly liver, muscle, fat). The receptor is a glycoprotein complex (350000MW)
consisting of two - and two -subunits linked by disulfide bridges. The -subunits are
entirely extracellular and contain the insulin binding domain, while -subunits are
transmembrane proteins that posses tyrosine protein kinase activity.

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After insulin is bound the receptors aggregate and are rapidly internalized.
Tyrosine kinase gets autophosphorylated and also phosphorylates other substrates so that a
signaling cascade is initiated and biological response ensues.

Figure 1.1: Normal Insulin Signaling Pathways

1.6 Pathophysiology of diabetes:

Although several pathogenic processes may be involved in the development of

diabetes, the vast majority of cases fall in to two categories: type 1 and type 2 Diabetes
Mellitus. There are genetic and environmental components in both types of DM. Type 1
DM occurs usually due to genetic predisposition and immune mediated destruction of
pancreatic islet β-cells with consequent loss of insulin secretion followed by prediabetes
and overt diabetes.

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Type 2 DM results from a combination of relative deficiency in insulin production

from the beta cell and insulin resistance at the target cell (liver, muscle and fat). Owing to
heterogeneous nature of NIDDM and two major pathogenic factors influence one another,
it is difficult to determine which of the two is initializing factor and what is relative
contributions to the development of glucose intolerance.

1.7 Signs and symptoms:

Onset of type 1 DM is sudden and characterized by polyurea, polydipsia,

polyphagia, weight loss, decreased muscle strength, irritability and perhaps a return of
bed-wetting. The presentation may be ketosis. The clinical presentation of type 2 diabetes
mellitus may be insidious onset of weight loss, nocturia, vascular complication, decreased
or blurred vision, fatigue, anemia or signs and symptoms of neuropathy. The diagnosis of
diabetes mellitus is based on the documentation of elevated fasting blood glucose, elevated
blood glucose two hours postprandly, or an abnormal glucose tolerance test.

 Complication:

A well control diabetic is less labile to ketosis and infections. It is now certain that
good control of glycemia mitigates the serious microvascular complications, retinopathy,
nephropathy and cataract. Too light control of glycemia can increase the frequency of
attacks of hypoglycemia.
Diabetic ketoacidosis is caused by insulin deficiency and an increase in catabolic
hormones, leading to hepatic overproduction of glucose and ketone bodies. Hyperglycemia
causes a profound osmotic diuresis leading to dehydration and electrolyte loss, particularly
of sodium and potassium. The metabolic acidosis forces hydrogen ions into cells,
displacing potassium ions, which may be lost in urine or through vomiting. The signs and
symptoms include polyuria, weight loss, thirst, abdominal pain, nausea, and vomiting.
Hypotension, hypothermia and air hunger may also be present.
Nonketotic hyperosmolar coma is characterized by severe hyperglycemia (>50
mmol/l) without significant hyperketonemia or acidosis. This condition usually affects
elderly patients, many with previously undiagnosed diabetes. Mortality is over 40%.

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Fig 1.2: Complications of Diabetes mellitus

Diabetic retinopathy is the most common cause of blindness in adults between 30

and 65 years of age in developed countries. Clinical features of diabetic retinopathy
include microaneurysms, retinal haemmorhages, hard exudates, soft exudates and fibrosis.
Cataracts also are associated with the disease.
Diabetic neuropathy occurs mainly due to axonal degeneration of both myelinated
and unmyelinated fibres (Axonal shrinkage, Axonal fragmentation; regeneration),

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thickening of schwan cell basal lamina, patchy segmental demyelination and abnormalities
in intraneural capillaries. This is relatively early and common complication affecting
approximately 30% of diabetic patients.
Diabetic foot occurs as a result of trauma in the presence of neuropathy and / or
peripheral vascular disease, with infection occurring as a secondary phenomenon
following ulceration of protective epidermis. In most cases all the three components are
involved but sometimes neuropathy or ischaemia may predominate.

In Diabetic nephropathy pathologically the first changes (at the time of

microalbuminurea) are thickening of glomerular basement membrane and accumulation of
matrix material in the mesangium. Subsequently, nodular deposits are characteristic, and
glomerulosclerosis worsens (time of heavy proteinurea) glomeruli are progressively lost
and renal function deteriorates.

1.8 History
Diabetes mellitus is known to the human beings many years ago mainly from
prehistoric times. In earlier day, a clinical diagnosis of diabetes was an invariable death
sentence, more or less quickly. Even non-progressing type 2 diabetes was left
undiagnosed. But with the discovery of insulin, its treatment is made possible. Diabetes
was first identified by Egyptians about 3500 years ago. It has been explained in the
medical books of the ancient civilizations of Egypt, Greece, Indian, Rome and China. In
the ancient books it has been mentioned that the disease is associated with polyuria,
polydipsia, polyphagia, etc. A Roman citizen has described diabetes as a melting down of
the flesh and limbs into urine. Moreover, the Charaka and Sushruta well known Ayurvedic
physician, described that the diabetic patients’ passes sweet urine in large amount that is
rain of honey.

So, They have named Diabetes mellitus as “Madhumeha”. Thereafter, we can say
diabetes has been recognized since antiquity, and its treatments were known since the
middle ages. But the etiopathogensis of diabetes occurred mainly in the 20thcentury. The
ancient Chinese have tested for diabetes by observing whether ants were attracted to a
person’s urine or not. Medieval European doctors have tested for diabetes, by testing the
urine of diabetic patients themselves, a scene occasionally depicted in Gothic relief, and
they named it “sweet urine disease”.

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1552 B.C.  Earliest known record of diabetes mentioned on 3rd

Dynasty Egyptian papyrus by physician Hesy-Ra;
mentions polyuria (frequent urination) as a symptom.
1st Century A.D.  Diabetes described by Arateus as 'the melting down of
flesh and limbs into urine.'
164 A.D.  Greek physician Galen of Pergamum mistakenly
diagnoses diabetes as an ailment of the kidneys.
Up to 11th  Diabetes commonly diagnosed by 'water tasters,' who
Century drank the urine of those suspected of having diabetes;
the urine of people with diabetes was thought to be
sweet-tasting. The Latin word for honey (referring to
its sweetness), 'mellitus', is added to the term diabetes
as a result.
16th Century  Paracelsus identifies diabetes as a serious general
disorder.
th
Early 19  First chemical tests developed to indicate and measure
Century the presence of sugar in the urine.
late 1850s  French physician, Priorry, advises diabetes patients to
eat extra large quantities of sugar as a treatment.
1870s  French physician, Bouchardat, notices the
disappearance of glycosuria in his diabetes patients
during the rationing of food in Paris while under siege
by Germany during the Franco-Prussian War;
formulates idea of individualized diets for his diabetes
patients.
th
19 Century  French researcher, Claude Bernard, studies the
workings of the pancreas and the glycogen metabolism
of the liver.
 Czech researcher, I.V. Pavlov, discovers the links
between the nervous system and gastric secretion,
making an important contribution to science's
knowledge of the physiology of the digestive system.

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Late 19th Century  Italian diabetes specialist, Catoni, isolates his patients
under lock and key in order to get them to follow their
diets.
1869  Paul Langerhans, a German medical student, announces
in a dissertation that the pancreas contains contains two
systems of cells. One set secretes the normal pancreatic
juice, the function of the other was unknown. Several
years later, these cells are identified as the 'islets of
Langerhans.'
1889  Oskar Minkowski and Joseph von Mering at the
University of Strasbourg, France, first remove the
pancreas from a dog to determine the effect of an
absent pancreas on digestion.
1900-1915  'Fad' diabetes diets include: the 'oat-cure' (in which the
majority of diet was made up of oatmeal), the milk diet,
the rice cure, 'potato therapy' and even the use of
opium!
1908  German scientist, Georg Zuelzer develops the first
injectible pancreatic extract to suppress glycosuria;
however, there are extreme side effects to the
treatment.
1910-1920  Frederick Madison Allen and Elliot P. Joslin emerge as
the two leading diabetes specialists in the United
States. Joslin believes diabetes to be 'the best of the
chronic diseases' because it was 'clean, seldom
unsightly, not contagious, often painless and
susceptible to treatment.'
1913  Allen, after three years of diabetes study, publishes
Studies Concerning Glycosuria and Diabetes, a book
which is significant for the revolution in diabetes
therapy that developed from it.
1919  Frederick Allen publishes Total Dietary Regulation in

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the Treatment of Diabetes, citing exhaustive case

records of 76 of the 100 diabetes patients he observed,
becomes the director of diabetes research at the
Rockefeller Institute.
1919-20  Allen establishes the first treatment clinic in the USA,
the Physiatric Institute in New Jersey, to treat patients
with diabetes, high blood pressure and Bright's disease;
wealthy and desperate patients flock to it.
October 31, 1920  Dr. Banting conceives of the idea of insulin after
reading Moses Barron's 'The Relation of the Islets of
Langerhans to Diabetes with Special Reference to
Cases of Pancreatic Lithiasis' in the November issue of
Surgery, Gynecology and Obstetrics. For the next year,
with the assistance of Best, Collip and Macleod, Dr.
Banting continues his research using a variety of
different extracts on de-pancreatized dogs.
Summer 1921  Insulin is 'discovered'. A de-pancreatized dog is
successfully treated with insulin.
December 30,  Dr. Banting presents a paper entitled 'The Beneficial
1921 Influences of Certain Pancreatic Extracts on Pancreatic
Diabetes', summarizing his work to this point at a
session of the American Physiological Society at Yale
University. Among the attendees are Allen and Joslin.
Little praise or congratulation is received.
1940s  Link is made between diabetes and long-term
complications (kidney and eye disease).
1944  Standard insulin syringe is developed, helping to make
diabetes management more uniform.
1955  Oral drugs are introduced to help lower blood glucose
levels.
1959  Two major types of diabetes are recognized: type 1
(insulin-dependent) diabetes and type 2 (non insulin-

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dependent) diabetes.
1960s  The purity of insulin is improved. Home testing for
sugar levels in urine increases level of control for
people with diabetes.
1970  Blood glucose meters and insulin pumps are developed.
 Laser therapy is used to help slow or prevent blindness
in some people with diabetes.
1983  First biosynthetic human insulin is introduced.
1986  Insulin pen delivery system is introduced.
1993  Diabetes Control and Complications Trial (DCCT)
report is published. The DCCT results clearly
demonstrate that intensive therapy (more frequent
doses and self-adjustment according to individual
activity and eating patterns) delays the onset and
progression of long-term complications in individuals
with type 1 diabetes.
1998  The United Kingdom Prospective Diabetes Study
(UKPDS) is published. UKPDS results clearly identify
the importance of good glucose control and good blood
pressure control in the delay and/or prevention of
complications in type 2 diabetes.

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2. REVIEW ARTICLES21-39
2.1 History
The discovery of insulin in 1922 by Benting, Best, Mac Leod and Collip,
confirmed on the one hand the role of pancreas as an endocrine gland and the part it plays
in the pathogenesis of diabetes, a fact which had also been indicated initially by the
research of Minkowisky and of Hedon. Insulin was isolated in the crystalline form by Abel
in 1926. On the other hand it provided many diabetic patients with an effective form of
treatment allowing them to lead almost normal lives.
It is immediately apparent that insulin did not cure diabetes, that its beneficial
effects did not last more than a few hours, that injections needed to be repeated throughout
the day and that such treatment would have to be carried out immediately. It was also
shown that insulin was rapidly inactivated when it was administered via the digestive tract.
Attempts to treat human diabetes by orally administered pharmacological agents
like synthalins and their derivatives, were made between 1925 to 1930, these substances
were quickly abandoned by their advocates however because of their variability, the
appearance of toxic side effects and of the uncertainty concerning their mode of action.
After the earlier therapeutic failures of the synthalins, attempts were made
to prolong the 6-8 hour effects of the single injection of soluble insulin to obviate the
necessity for repeated injections. This was done by coupling the hormone to zinc and then
to certain protamines, which are other agents, prolonging the effects of ordinary insulin,
producing protamine-zinc-insulin (PZI), which after a single injection could maintain
effects for 24 hrs in certain cases, longer.
Between 1939 and 1942, the therapeutic use of the sulfonamide increased dramatically and
the drugs were assessed end tried in the treatment of many infectious diseases.
CH3
SO2NH S
H 2N
CH3
N N
VK-57 (2254RP)

P-amino-benzene-sulfonamide-isopropyl-thiadiazole (VK-57) was synthes -ized in

1941 by Von Kennel and Kimming. This drug had shown a certain in vitro inhibitory

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effect on multiplication of the typhoid bacillus. After oral doses of 2254RP some patients
died from obscure causes, which were only elucidated later when the hypoglycemic action
of the sulfonamide became clear, it was strongly suggested that they died from severe and
prolonged hypoglycemia.
Several experiments were done in different animal models to explain the
hypoglycemic effect of sulfonamide. It was postulated that sulfonamide act by stimulating
the beta cells of the islets and liberate in to the blood an accumulated quantity of
endogenous insulin (insulin secretory action).

H2N SO2NHCONHCH2CH2CH2CH3

Carbutamide (BZ55)

German workers published that a new sulfonamide i.e.1-butyl-3-sulfonylurea

(carbutamide or BZ55) was more active than 2254 RP as hypoglycemic agent. 2254 RP
and carbutamide have a NH2 group in the para position on the benzene ring and because of
this have a bacteriostatic action, which could be considered unnecessary if not a major
disadvantage.
In 1956, a group of german workers published the experimental and clinical
results obtained by using a sulfonamide with its NH2 group in the para position replaced
by CH3 group but with the reminder of the molecule possessing a structure identical to that
of carbutamide. This substance D860, 1-butyl-3-tolyl-sulfonylurea (tolbutamide) which
did not have bacteriostatic action and retained the hypoglycemic and antidiabetic
properties of 2254RP and carbutamide.

H3C SO2NHCONHCH2CH2CH2CH3

Tolbutamide

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2.2 Oral Antidiabetic Agents (Clinically used)

1) Sulfonylureas:

Since 1956 till present sulfonylureas class of compounds are used for the treatment
of diabetes mellitus. Modifications were made to improve the potency of the compounds
and avoid toxic effects. A wide variety of structural modifications have been carried out on
the original Carbutamide, tolbutamide, chlorpropamide type sulfonylureas which led to
tolazamide, gliclizide, acetohexamide, gibornuride, glimidine, tolcyclamide etc. These
sulfonylureas were termed as first generation sulfonylureas. Further research in this area
led to potent antidiabetic agent, glibenclamide (gliburide, glibiride, and glybencyclamide,
HB-419) and other compounds like glipizide, glisepoxide, gliquidone, glypentide etc,
which are termed as second-generation sulfonylureas.

A-SO2-NH-B

 First generation sulfonylureas:

First generation sulfonylureas are less potent and act at higher dose. Some of useful
compounds and their structures are:

Cl SO2NHCONHCH2CH2CH3

Chlorpropamide

H3C SO2NHCONH N

Tolazamide

OMe SO2NHCONH

Acetohexamide

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H3 C SO2NHCONH N

Gliclizide
 Second-generation sulfonylureas:

Second generation sulfonylureas are very potent compounds and their dose is low.
Some examples are as follows:
OMe

CONHCH2CH2 SO2NHCONH

Cl

Glibenclamide

N
H3C CONHCH2CH2 SO2NHCONH
N

Glipizide
2) Biguanides:
The only nonsulfonylurea drugs, which have proven useful in antidiabetic therapy,
are the biguanides17, which can be used either alone or in combination with sulfonylureas.
Only three agents are marketed at the present time (Metformin, Chenformin and
Buformin).
NH NH
H3C
N C NH C NH2
H3C

Metformin

NH NH

H2CH2C NH C NH C NH2

Phenformin (Chenformin)
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 ANTI-DIABETIC AGENTS

NH NH

H3CH2CH2CH2C NH C NH C NH2

Buformin

Two factors have recently emerged which adversely affect the use of biguanides.
Phenformin was one of the drugs examined in the university group Diabetes program
(UGDP) study and as in the case of tolbutamide, enhanced cardiovascular mortality was
observed instead of the anticipated beneficial effects. These findings were judged to be
severe enough to warrant an early termination of phenformin study. Again, the conclusion
of the UGDP study group have aroused controversy, and its conclusions have been
questioned. It is certainly interesting that a group from England found a reduced incidence
of myocardial infarction in a 5-year study of phenformin and that another group found a
slight but insignificant beneficial effects of phenformin on survival in patients with
coronary heart disease. It is therefore not clear at this time whether the use of phenformin
is associated with increased cardiovascular mortality only in diabetes or whether the
findings with phenformin can be generalized to other biguanides.

2.3 Oral Antidiabetic Agents (Clinically not used)

1) Carboxylic Acids:

An interesting newer structure is meglitinide (HB-669), which is related to

Glibenclamide, with a carboxyl group replacing the acidic sulfonylurea function. HB-669
and its higher homologue (HB-093) are insulin releasers although their potency is much
more than that of Glibenclamide and more in the range of tolbutamide. It should be
interesting to see whether or not will prove efficacious in man. Similarly, a benzoic acid
derivative has hypoglycemic properties, and the S-enantiomer is more potent than R-
enantiomer. This suggest that the high potency side chain of both sulfonylureas and
benzoic acids interact at the same receptor.

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 ANTI-DIABETIC AGENTS

OMe

CONHCH2CH2 COOH

Cl
Meglitinide

OMe

CONHCH2CH2 CH2CH2COOH

Cl

HB-669

2) Benzoic Acid Derivatives: (S-enantiomer)

OMe
H
NHCOCH2 COOH
CH3
F
Salicylates have been used long ago to improve glucose control in diabetes,
possibly via their insulin-releasing or antilipolytic effects. However, high doses are
required and the clinical benefits appear to be marginal.

OH H3C OH

COOH COOH

The benzoic acid derivatives have been reported to stimulate glucose utilization,
but it apparently had side effects and caused tachyphylaxis in animals.

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COOH
Cl N

3-Mercaptopicolinic acid and several derivatives are apparently gluconeogenesis

inhibitors, which lower glucose levels in animals.
SH

N COOH

3) Heterocyclic Carboxylic Acid:

A series of heterocyclic carboxylic acids and their metabolic precursors generated
some excitement a few years ago because these antilipolytic compounds lowered blood
glucose in diabetics.

4) Heterocyclic Acids:
H3C

N COOH
O

5) Metabolic precursors of above Heterocyclic Acids:

H3C
H3C

N
N CH3 N
H O CH3

6) Aliphatic Carboxylic Acids:

Among aliphatic carboxylic acids, dichloroacetic acid in the form of its
diisopropylammonium or sodium salt, has been shown to lower blood glucose and to
remedy the lactate elevations found after phenformin treatment.

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7) Dichloroacetic Acid:
Cl2CHCOOH
8) Diisopropyl Derivative:
HOOCCOCH2COOH

9) Oxirane Carboxylic Acid:

Oxirane carboxylic acid and its methyl esters are reported to be inhibitors of
carnitine acyl transferase and to be hypoglycemic in fasted, diabetic, or fat fed animals, by
enhancing peripheral glucose oxidation.

H29C14 COOH H29C14 COOCH3

O O
NH2

COOH COOH

10) Amidines and Guanidines:

Among non-acidic hypoglycemic agents, there are several intriguing guanidines
and amidines. Pirogliride, although its structure is somewhat reminiscent of biguanides, is
reported to have a different activity profile and mechanism of action.

N
N N N
CH3

Pirogliride

Cetpiperalone is piperazine derivative related to cyclic guanidines and has the

potency range of tolbutamide, is probably an insulin releaser.

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NH

N N NH
H

Cetpieralone
A series of alpha alkoxy amidines. Displayed hypoglycemic and nutiuretic activity
in animals, but poor separation of activity from toxicity exhibited by these compounds
prevented clinical studies.
H3CH2CO N

N
H

-Alkoxy amidines
11) Fatty acid Oxidation Inhibitors:
Its use as orally effective hypoglycemic compounds has its roots in Randles
glucose-fatty acid cycle first proposed in the 1960’s. This hypothesis recognized the
reciprocal relationship that exists between fat and carbohydrate metabolism. A reduction
in fatty acid oxidation should enhance carbohydrate utilization and consequently lower
blood glucose levels.

12) Carnitine Palmitoyl Transferase (CPT):

Most inhibitors of this enzyme reported in the literature are long chain fattyacyl
CoA analogues. The two most thoroughly characterized CPT inhibitors are TDGA (2-
tetradelylglycidate) and its methyl ester (MeTDGA) and POCA
(chlorophenylpentyoxirane carboxylate).

CH3(CH2)13 COOH

O
COOH

O
Cl
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 ANTI-DIABETIC AGENTS

Emeriamine is a carnitine analogue, which has significant hypoglycemic effects in

fasted rats and several other animal models. Another novel compound, 2-(3-
methylcinnamylhydrazono) propionate (MCHP) apparently inhibits the translocation of
long chain fattyacyl carnitines across the mitochondrial membrane but has little or no
effect on either CPT or CPT ІІ.
CH3
H3C N CH2 CH CH2 COOH
CH3

Emeriamine

CH3
HC CH2 NH N
CH3 COOH

MCHP

13) Hydrazinopropionic Acids:

Over 20 years ago, monoamine oxidase inhibitors of the hydrazine type were
proposed as supplementary hypoglycemic agents for the treatment of diabetes mellitus.
They found two hydrazine analogues, (2-phenylethylhydra-zino) and 2-
(cyclohexylethylhydrazino) propionic acids (PEHP and CHEHP, respectively), with
increased hypoglycemic activity and reduced toxicity.

CH3
H2C H2C NH N
COOH

Both compounds at dose of between 145 and 800 μmol / kg (30 and 170 mg / kg,
respectively) significantly lowered blood glucose in 48 hours fasted guinea pigs, rats and
hamster. Glucose lowering effects were also observed in 12 hr fasted diabetic mice.

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 ANTI-DIABETIC AGENTS

CH3
H2C H2C NH N
COOH

PEHP

Another novel hypoglycemic agent AS-6, is derived from ascochlorin which was
first discovered in the filter cake of the fermented broth of the fungus. Ascochytavivia
Libert. AS-6, the 4-0-carboxymethylated derivative of ascochlorin, is a more potent
hypoglycemic agent and is more readily absorbed.
OH CH3 CH3
OHC O

H3C O H3C
Cl CH2
COOH
AS-6
14) β-Adrenergic agonist:
The utility of β-Adrenergic agonists as hypoglycemic agents has been surprising,
since acute administration of isoproterenol (isoprenaline) or the more selective β2-agonist,
terbuteline, caused deterioration in glycemic control in humans.
OH CH3
H2
CH CH2 NH CH C

COOCH3

BRL-26830

New β-adrenergic agonists have been designed for their utility in treatment of
obesity and NIDDM, as opposed to the traditional antiasthematic β2-agonists. A subset of
β-adrenergic receptors that dose not fall clearly in to either β1 or β2 has been described in
rat brown adipose tissue. Selective activation of this receptor, by chronic administration of

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BRL-26830 to genetically obese (57 BL/6, ob/ob) mice, stimulated the metabolic activity
of brown adipose tissue, elevated caloric consumption and resulted in a highly significant
reduction in weight gain.
A second β-adrenergic agonist with potential utility in the improvement of insulin
sensitivity is Ro-16-8714. When obese mice (C57BL/6J, ob/ob) received this agent for 15
days, glycosuria rapidly diminished and blood glucose was normalized, while circulating
insulin levels were not altered.

OH
OH
CH CH2 O
N CH CH2 CH2 NH2
CH CH2

OH

Ro-16-8714

15) Anorectic agents:

Weight loss in the treatment of obese NIDDM is often an effective means of
achieving improved glycemic control. When diet therapy alone is inadequate to initiate the
weight reduction program variety of anorectic agents are available for short-term therapy.
Two of the agents, mazindol and fenfluramine, may also possess activities which improve
glucose control independent of the weight loss they reduce.
OH
OH
CH CH2 O
N CH CH2 CH2 NH2
CH CH2

OH
Mazindol
Ciclizindol, a drug structurally related to mazindole, also stimulated glucose uptake
in to human skeletal muscle in both the presence and absence of insulin.

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 ANTI-DIABETIC AGENTS

Cl

HO
N

Ciclazindol
Fenfluramine is an anorectic agent structurally similar to amphetamine, but with a
mechanism of action relating to its 5-hydroxytryptamine- agonistic activity, which
distinguishes a from the amphetamine class of drugs.
CH3

CH2 CH NH CH2 CH3

CF3

Fenfluramine
16) Steroids:
Dehydroepiandrosterone (DHEA) is a major secretory product of the adrenal
cortex, which ameliorates several metabolic abnormalities found in obese, insulin resistant
rodents.40 Substantial improvement in glucose metabolism in insulin resistant rodents, has
been demonstrated with chronic dosing of DHEA and its metabolites. Although DHEA
produces pronounced changes in glucose metabolism and insulin sensitivity, three
metabolic products of DHEA, 3-tetrahydroxyetiocholanolone (tetra-ET), 3-α-
hydroxyetiocholano lone (Beta- ET), β-hydroxyetiocholanolone (β-ET) and DHEA sulfate,
are more potent hypoglycemic agents.

O O

HO HO

DHEA 3-α-hydroxyetiocholanolone

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 ANTI-DIABETIC AGENTS

HO
3-β-hydroxyetiocholanolon

17) Miscellaneous Agents:

The anorectic agent fenfluramine has been shown to improve glucose tolerance and to
lower fasting blood sugar in diabetes in numerous studies. A fenfluramine analogue, 780
SE has also been shown to improve tolerance in insulin-independent diabetics, Potential of
insulin mediated glucose utilization in the periphery has also been postulated as the
mechanism of action.

CH3

CH2 CH NH CH2 CH3

CF3

Fenfluramine

CH3

CH2 CH H

CF3 NHCH2CH2O CO

780 SE

The hypoglycemic agent halofenate at a dose of 500-1500 mg daily reduces the

requirements for sulfonylureas in diabetics, and this effect seems to be mediated by
interference with the metabolism of the sulfonylurea and not by a direct hypoglycemic
effect.

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CF3 O
NH COCH3
COOH
Cl
Halofenate

The hypoglycemic drug clofibrate on the other hand, which also transiently
potentiates the effects of sulfonylureas at a dose of 1000 mg bid, has been shown to lower
fasting and postprandial glucose in diabetics when given alone in a 7 day study,
supposedly by increasing insulin sensitivity; however; it had no effect on fasting blood
glucose in longer term (48 weeks) studies.

CH3
O CH3
COOCH2CH3
Cl

Clofibrate
Experiments in normal subjects suggested that the glycosidase and amylase
inhibitor acarbose (BAY 5421, 60), used at about 75 mg, should be of value in decreasing
postprandial blood glucose peaks.

HOCH2 H3C HOCH2 HOCH2

O O O
HO NH O O OH

HO OH HO OH HO OH HO OH

Acarbose

A study in diabetics showed that addition of 6 times 50 mg of daily to the usual

sulfonylurea or insulin regimen led to a further decrease in blood glucose values.
Somatostatin a tetrapeptide which was originally isolated from hypothalamus, but which
occurs also in the D-cell of the pancreas, suppresses the secretion of growth harmone,
glucagons and insulin dependent diabetics, but caused only a transient hypoglycemia

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followed by hyperglycemia in NIDDM. Analogues of such as are of value in management

of diabetes.

1 2 3 4 5 6 7 8 9 10 11 12 13 14
H-Ala-Gly-Cys-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Ser-Cys-OH

 2,4-Thiazolidinediones:

A recent new class of oral hypoglycemic drugs thiazolidinediones was found to be

effective against noninsulin dependent diabetes mellitus. Its development started many
years ago and still a lot of work is left with this class of compounds.
In 1980 Kawamatsu, Y.; Saraie, E. found that ethyl 2-chloro-3-[4-(2-methyl-2-
phenylpropoxy) phenyl] propionate (AL-294) was effective against hyperglycemia and
hyperlipidemia in genetically obese and diabetic mice, yellow KK, which develop glucose
and lipid dismetabolism associated with severe insulin resistance.
CH3
H
CH2O C C COOCH2CH3
H2
CH3 Cl

AL-294
In 1982 Shohda, Takashi.; Kawamatsu, Y. from Takeda Chemical Industries Ltd.
Osaka, Japan developed a series of compounds containing 4-(2-methyl-2-phenylpropoxy)
benzyl moity and evaluated their hypoglycemic and hypolipidemic activities with
genetically obese and diabetic mice, yellow KK. Among these compounds 5-[4-(2-methyl-
2-phenylpropoxy) benzyl] thiazolidine-2, 4-dione (AL-321) was found to possess
hypoglycemic and hypolipidemic activities higher than AL-294.

CH3 O

CH2O
NH
CH3 S
O
AL-321

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In the same year more than 100 5-substituted thiazolidine-2, 4-dione were prepared
and their hypoglycemic and hypolipidemic activities were evaluated with genetically
obese and diabetic mice, yellow KK. Among these compounds 5-{4-[2-(3-pyridyl) ethoxy]
benzyl} benzyl] thiazolidine-2, 4-dione (ADD-3878, ciglitazone) exhibited most favorable
activity.
O

H2
NH
C S
O
CH3 O

ADD-3878 (Ciglitazone)
In 1982 Shohda, T; Kawamatsu, Y. from Takeda Chemical Industries Ltd. and
Senju Pharmaceutical Co., Ltd. Japan synthesized and evaluated thiazolidine-2, 4-dione
having substitution at 5-position for Aldose Reductase Inhibitors.

In 1984 Shohda, T; Kawamatsu, Y. of Takeda Chemical Industries Ltd. Osaka,

synthesized compounds having hydroxy and an oxo moity on the cyclohexane ring of
ciglitazone to clarify the structure of the metabolites of ciglitazone and for studies of their
pharmacological properties. Of the metabolites identified, 5-[4-(t-3-hydroxy-1-
cyclohexylmethoxy) benzyl] thiazolidine-2, 4-dione exhibited extremely potent
antidiabetic activity compared to ciglitazone.

NH
R S
O
O R=…

O HO H2 HO H2
H2 H2
C C C C
O CH3
CH3 CH3 CH3

4’-oxo cis-4’-ol trans-4’-ol 3’-oxo

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H2 H2 H2 H2
C C C C
HO CH3 CH 3 HO
CH3 O OH CH3

trans-3’-ol 2’-oxo 2’-ol cis3’-ol

In 1986 Meguro, K; Fugita, T.; Shohda, T. of Takeda Chemical Industries Ltd.

Osaka, Got a US patent (4,687,777) as well as European patent (0193256) for some
thiazolidedione derivatives of formula given as (A) exhibited blood sugar and lipid
lowering activity in mammals.
O

C2H5 NH
N O S
O

(A)
In 1989 Yoshioka, T.; Fujita, T; Kanai T. et al. at Sankyo Co., Ltd. Japan
investigated series of hindered phenols hypolipidemic and/or hypoglycemic agents with
ability to inhibit lipid peroxidation. Among the compounds of this series (f)-5-[4-[(6-
hydroxy-2, 5, 7, 8-tetramethylchroman-2-yl) methoxy]-benzyl]-2, 4-thiazolidinedione
(CS-045) was found to have all of our expected properties and was selected as a candidate
for further development as a hypoglycemic and hypolipidemic agent.
O

HO S NH
O
O
O

Troglitazone (CS-045)

In 1990 Zask, A.; McCaleb, M. L. of Wyeth-Ayerst Research, New Jersey

synthesized a series of (naphthalenylsulfonyl)- 2, 4-thiazolidinedione and evaluated for
antihyperglycemic activity in insulin-resistant, genetically diabetic db/db mouse model of
non-insulin dependent diabetes mellitus (NIDDM). The best analogue (AY-31637) was
equipotent to ciglitazone.

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O
SO2
NH
S
O
(AY-31637)

In 1991 Clark, D. A.; Goldstein, S. W of Central Research, Pfizer, Groton

synthesized Dihydrobenopyran and dihydrobenzofuran thiazolidedione-2, 4-diones. These
compounds represent conformationally restricted analogues of novel hypoglycemic
ciglitazone. Among the compounds of this series englitazone (CP-68722, CP-72466) was
proved to be efficacious in terms of activity.
O

S NH
O
O
Englitazone (CP-68722, CP-72466)
In 1991 Ammos, Y; Shohda, T. synthesized various analogues of Pioglitazone
(AD-4833, U-72107). Several 5- [4-(2-(2-pyridyl) ethoxy] benzylidine]-2,4-
thiazolidinediones were equipotent to pioglitazone however; the thia analogues and
benzylidine heterocycles had decreased activity.
O
N
S NH
O
O
Pioglitazone (AD-4833, U-72107)

In 1992 Shohda, T.; Fugita. T. of Takeda Chemical Industries Ltd. Osaka,

synthesized a series of 5- [4-(2-(2-pyridyl) ethoxy] benzylidine]-2, 4-thiazolidinediones as
modification of the novel antidiabetic Pioglitazone (AD-4833, U-72107). Among the
compounds synthesized 5- [4-(2-(5-methyl-2-phenyl-4-oxazolyl) ethoxy] benzy]-2,4-

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thiazolidinedione (B) exhibited the most potent activity, more than 100 times that of
pioglitazone.
O
R1 X R2
NH
N S
Y (CH2)n O
O
(B)

In 1994 Barrie, C. C.; Thurlby, P. L. from SmithKline Beecham Pharmaceuticals,

UK synthesized a series of [[-(Hetro cyclyl amino) alkoxy] benzyl –2,4-
thiazolidinedionesantihyperglycemic activity together with effects on hemoglobin content
was performed in genetically obese C57 B1/6 ob/ob mice. From these studies BRL 49653
has been selected for further evaluation.
O
CH3
N NH
O S
N
O
BRL 49653
In 1998 Lohray, B. B.; Rajagopalan, R. of Dr. Reddy’s Research Foundation,
Hyderabad, India synthesized a series of [[(heterocyclyl) ethoxy] benzyl]-2,4-
thiazolidinediones. Many of these compounds have shown superior euglycemic and
hypolipidemic activity compared to troglitazone (CS045). The indole analogue DRF-2189
was found to be more potent insulin sensitizer, compared to BRL-49653 in genetically
obese C57BL/6J-ob/ob and 57BL/KS-db/db mice.
O

N NH
O S
O
DRF-2189

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In 1999 Lohray, B. B.; Rajagopalan, R. Dr. Reddy’s research foundation,

Hyderabad, India synthesized substituted pyridyl- and quinolinyl-containing 2, 4-
thiazolidinediones having cyclic amine as a linker and evaluated hypoglycemic and
hypolipidemic activity and compared with BRL-49653. Among all the salts evaluated, the
maleate salt of unsaturated TZD (5a) was found to be euglycemic and hypolipidemic
compound.

O
N
N
NH
O S
O

(5a)

In 1999 Nomura, M.; Miyachi, H. of Kyorin Pharmaceutical Company, Japan

prepared a series of (3-substituted benzyl) thiazolidine-2, 4-dione which led to the
identification of (KRP-297) as a candidate for the treatment of diabetes mellitus.
O O
CH2 CH2
NH
H S
CF3 CH3O O

KRP-297

In 2000 Oguchi, M.; Fugita, T. of Sankyo company, Ltd., and sankyo pharma
research institute, California designed and synthesized a series of Imidazopyridine
thiazolidine-2, 4-diones and evaluated for its effect on Insulin induced 3T3-L1 adipocyte
differentiation invitro and its hypoglycemic activity in genetically diabetic KK mouse in
vivo.
R4
O
R3
N
NH
R2 N N O S
R1 O
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 ANTI-DIABETIC AGENTS

R1= H, Me, Et, Ph, 4-Cl-C6H4CH2, R2= H, Me, Cl, OH, etc
R3= H, Cl, Br, CF3, R4= = H, Me

In 2003 Desai, R. C.; Berger, J. P.; Kwan, L. of Merck Research Laboratories,

USA synthesized a number of potent 5-aryl thiazolidine-2, 4-diones and performed
efficacy studies which showed them superior to rosiglitazone in correcting hyperglycemia
and hypertriglyceridemia.
O
O

NH
O O S
O

5-aryl thiazolidine-2, 4-diones

In 2004 Bhatt, A. B.; Srivastava, A. K. from CDRI, Lucknow synthesized a

number of thiazolidinedione derivatives having carboxylic ester appendage at N-3 and
evaluated their hypoglycemic activity. N-carboalkoxymethylthiazolidine-2, 4-diones was
selected as core structure with substituted benzylidine and benzyl and heteroaryl
derivatives.
O
O
R Z
N OX
S
O
N-carboalkoxymethylthiazolidine-2, 4-diones
R=C6H5OH, C6H5CF3, C6H5CH3, C6H5Cl etc.
X=CH2CH3, CH3
Z=Single Bond, Double Bond

Iqbal, Javed. of Dr. Reddy’s Laboratories, Hyderabad, India designed TZD

derivatives, which can reduce plasma glucose with less adipogenesis. The SAR of these
TZD derivatives gave Balaglitazone which has 70% of PPAR- transactivation compared to
rosiglitazone and showed partial agonism in competitive binding assay. Balaglitazone has
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shown good efficacy in db/db and ob/ob mice models at 3mg/kg. In zucker fa/fa rats it
shows insulin sensitization effects by 70% reduction in insulin and 80% reduction in free
fatty acids at 3mg/kg dose. Balaglitazone is now in phase-II clinical trials.
The literature, found for this class of drugs shows that there is a lot of advancement
in the development of a novel analogues of thiazolidinedione for the treatment of
noninsulin dependent diabetes mellitus and it is also clear that there has been abundant
research activity in this field globally. Several approaches have been attempted and some
new approaches are still emerging.

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3. CLASSIFICATION

1. Insulin
2. Secretagogues
2.1. Sulfonylureas
2.2. Meglitinides
3. Sensitizers
3.1. Biguanides
3.2. Thiazolidinediones
4. Alpha-glucosidase inhibitors
5. Peptide analogs
5.1. Incretin mimetics
5.1.1. Glucagon-like peptide (GLP) analogs and agonists
5.1.2. Gastric inhibitory peptide (GIP) analogs
5.1.3. Protein Tyrosin Phosphate 1β inhibitors
5.2. DPP-4 inhibitors
5.3. Amylin analogues

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Oral anti-diabetic drugs and Insulin analogs

Biguanides
Metformin ·Buformin‡ ·Phenformin‡

Pioglitazone · Rivoglitazone† · Rosiglitazone

Sensitizers TZDs (PPAR)
· Troglitazone‡
Dual PPAR
Aleglitazar† · Muraglitazar§ · Tesaglitazar§
agonists
1stgeneration: Acetohexamide
·Carbutamide ·Chlorpropamide
· Gliclazide · Tolbutamide
· Tolazamide
K+ ATP Sulfonylureas
2nd generation: Glibenclamide
( Glyburide) · Glipizide
· Gliquidone · Glyclopyramide
Insulin 3rd generation: Glimepiride
Secretagogues
Meglitinides/ Nateglinide · Repaglinide
Glinides · Mitiglinide

GLP-1
analogs Exenatide · Liraglutide · Albiglutide†

DPP-4 Alogliptin† ·Linagliptin† · Saxagliptin · Sitagliptin

inhibitors · Vildagliptin
. fast acting : (Insulin lispro · Insulin aspart · Insulin glulisine)
Analogs/other · Short acting : (Regular insulin)
insulins · long acting : (Insulin glargine · Insulin detemir) · Inhalable insulin
(Exubera)‡ · NPH insulin
α-glucosidase
Acarbose · Miglitol · Voglibose
inhibitors
Amylin
analog Pramlintide
Other
SGLT2
Dapagliflozin† · Remogliflozin† · Sergliflozin†
inhibitor
Other
Benfluorex · Tolrestat‡

‡ † §
Withdrawn from market. CLINICAL TRIALS: Phase III. Never to phase III

Table No. 1- Oral anti-diabetic drugs and Insulin analogs

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4. INSULIN
Sanger (in 1950s) put forward the primary structure of insulin as below in Figure.

20

20

Figure 4.1 Primary structure of proinsulin, depicting cleavage sites to produce

insulin.

The above Figure has the following Salient Features, namely:

(1) Proinsulin is the immediate precursor to insulin in the single-chain peptide.
(2) Proinsulin folds to adopt the ‘correct orientation of the prevailing ‘disulphide
bonds’ plus other relevant conformational constraints whatsoever on account of its primary
structure exclusively.
(3) Proinsulin in reality, has a precursor of its own, preproinsulin–a peptide, that
essentially comprises of hundreds of ‘additional residues’.

(4) At an emerging critical situation the insulin gets generated from proinsulin due
to the ensuing cleavage of proinsulin at the two points indicated. This eventually produces
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 ANTI-DIABETIC AGENTS

insulin, that comprises of a 21-residue A chain and strategically linked with two disulphide
bonds ultimately to a 30-residue B chain. Interestingly, these bondages between the two
aforesaid residual chains ‘A’ and ‘B’ are invariably oriented almost perfectly and correctly
by virtue of the prempted nature of proinsulin folding.

4.1 Description
Insulin is a hormone produced by the beta cells in the islets of Langerhans in the
pancreas.

Figure 4.2 Insuline structure

Insulin is used medically to treat some forms of diabetes mellitus. By reducing the
concentration of glucose in the blood, insulin is thought to prevent or reduce the long-term
complications of diabetes, including damage to the blood vessels, eyes, kidneys, and
nerves.

4.2 Variants of Insulin Products

There are a number of variants of insulin products that are available as follows:

4.2.1. Insulin Injection

4.2.1.1 Synonyms: Regular Insulin; Crystalline Zinc Insulin
It is available as a sterile, acidified or neutral solution of insulin. The solution has a
potency of 40, 80, 100 or 500 USP Insulin Units in each ml.
4.2.1.2 Mechanism of Action
It is a rapid-action insulin. The time interval from a hypodermic injection of this
drug until its action may be observed ranges between 1/2 to an hour. It has been observed
that the duration of action is comparatively short but evidently a little longer than the

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plasma half-life that stands at nearly 9 minutes. Importantly, the duration of action is not
linearly proportional to the size of the dose, but it is a simple function of the logarithm of
the dose i.e., if 1 unit exerts its action for 4 hours then 10 units will last 8 hours. In usual
practice the duration is from 8 to 12 hour after the subcutaneous injection, which is
particularly timed a few minutes before the ingestion of food so as to avoid any possible
untoward fall in the prevailing blood-glucose level.

4.2.2. Isophane Insulin Suspension

4.2.2.1 Synonyms: Isophane Insulin; Isophane Insulin Injection; NPH Insulin; NPH Iletin
The drug is a sterile suspension of Zinc-insulin crystals and protamine sulphate in
buffered water for injection, usually combined in such a fashion that the ‘solid phase of the
suspension’ essentially comprises of crystals composed of insulin, protamine*, and zinc.
Each mL is prepared from enough insulin to provide either 40, 80, or 100 USP Insulin
units of insulin activity.
4.2.2.2 Mechanism of Action
The drug exerts its action intermediate acting insulin for being insoluble and
obtained as repository form of insulin. In reality, the action commences in 1–1.5 hour,
attains a peak-level in 4 to 12 hour, and usually lasts upto 24 hours, with an exception that
‘human isophane insulin’ exerts a rather shorter duration of action. It is, however, never to
be administered IV.
4.2.2.3 Note: Incidence of occasional hypersensitivity may occur due to the presence of
‘protamine’.

4.2.3. Insulin Zinc Suspension

It is invariably obtained as a sterile suspension of insulin in buffered water for
injection, carefully modified by the addition of zinc chloride (ZnCl2) in such a manner that
the ‘solid-phase of the suspension’ comprises of a mixture of crystalline as well as
amorphous insulin present approximately in a ratio of 7 portions of crystals and 3 portions
of amorphous substance. Each mL is obtained from sufficient insulin to provide either 40,
80, or 100 USP Insulin Units of the Insulin Activity.

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4.2.3.1 Mechanism of Action

It has been duly observed that the ‘amorphous zinc-insulin component’ exerts a
duration of action ranging between 6–8 hours, whereas the ‘crystalline zinc-insulin
component’ a duration of action more than 36 hour, certainly due to the sluggishness and
slowness with which the larger crystals get dissolved. However, an appropriate dosage of
the 3 : 7 mixture employed usually displays an onset of action of 1 to 2.5 hour and an
intermediate duration of action which is very near to that of ‘isophane insulin suspension’
(24 hour), with which preparation this drug could be employed interchangeably without
any problem whatsoever. However, it must not be administered IV. The major advantage
of ‘zinc insulin’ is its absolute freedom from ‘foreign proteinous matter’, such as : globin,
or protamine, to which certain subjects are sensitive.

4.2.4. Extended Insulin Zinc Suspension

4.2.4.1 Synonyms: Ultra-Lente Iletin; Ultralente Insulin/Ultratard
4.2.4.2 Mechanism of Action
The actual ‘crystalline profile’ in this specific form are of sufficient size to afford
a slow rate of dissolution. It is found to exert its long-acting action having an onset of
action ranging between 4 to 8 hours, an optimal attainable peak varying between 10-30
hours, and its overall duration of action normally in excesss of 36 hours, which being a
little longer than that of Protamine Zinc Insulin.
4.2.4.3 Note: Because the drug is free of both protamine and other foreign proteins, the
eventual incidence of allergic reactions gets minimized to a significant extent.

4.2.5. Prompt Insulin Zinc Suspension

4.2.5.1 Synonyms: Semi-Lente Iletin ; Semitard
The drug is usually a sterile preparation of insulin in ‘buffered water for injection’,
strategically modified by the addition of zinc chloride (ZnCl2) in such a manner that the
‘solid phase of the prevailing suspension’ is rendered amorphous absolutely. Each mL of
this preparation provides sufficient insulin either 40, 80, or 100 USP Insulin Units.

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4.2.5.2 Mechanism of Action

The zinc-insulin in this particular form is a mixture of amorphous and extremely
fine crystalline materials. As a result, the drug serves as a rapid-acting insulin with an
onset of 1 to 1.5 hour, an attainable peak of 5-10 hours, and a duration of action ranging
between 12-16 hours.
4.2.5.3 Note: Since this specific form of insulin is essentially free of any foreign proteins,
the incidence of allergic reactions is found to be extremely low.

4.2.6. Lispro Insulin

4.2.6.1 Synonyms: Human Insulin Analog; Humalog
It is a human insulin analogue of r DNA origin meticulously synthesized from a
special nonpathogenic strain of E. coli, genetically altered by the addition of the gene for
insulin lispro ; Lys (B28), Pro (B29). In fact, the prevailing amino acids at position 28 and
29 of human insulin have been reversed altogether.
4.2.6.2 Mechanism of Action
The drug is very rapid-acting insulin which may be injected conveniently just
prior to a meal. It exhibits an onset of action within a short span of 15 minutes besides
having a relatively much shorter peak ranging between 0.5 to 1.5 hour, and having
duration of action varying between 6 to 8 hours in comparison to the ‘regular insulin
injection’.

4.2.7. Protamine Zinc Insulin Suspension

4.2.7.1 Synonyms: Zinc Insulin ; Protamine Zinc Insulin Injection ; Protamine Zinc and
Iletin
The drug is a sterile suspension of insulin in buffered water for injection, that has
been adequately modified by the addition of zinc chloride (ZnCl2) and protamine sulphate.
The protamine sulphate is usually prepared from the sperm or from the mature testes of
fish belonging to the genus Oncorhynchus Suckley or Salmo Linne (Family : Salmonidae).
Each mL of the suspension prepared from sufficient insulin to provide wither 40, 80, or
100 USP Insulin Units.

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4.2.7.2 Mechanism of Action

The drug exerts a long-acting action having an onset of action of 4 to 8 hour, a
peak at 14 to 24 hour, and a duration of action nearly 36 hour. As a result this drug need
not be administered with any definite time relation frame to the corresponding food intake.
Besides, it should not be depended upon solely when a very prompt action is required,
such as : in diabetic acidosis and coma. Since the drug possesses an inherent prolonged
action, it must not be administered more frequently than once a day. It has been duly
observed that ‘low levels’ invariably persists for 3 o 4 days; and, therefore, the dose must
be adjusted at intervals of not less than 3 days. It is given by injection, normally into the
loose subcutaneous tissue.
4.2.7.3 Note: The drug should never be administered IV.

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5. Secretagogues

5.1 K+ ATP

5.1.1 Sulfonylureas
The sulfonylurea hypoglycemic agents are basically sulphonamide structural
analogues but they do not essentially possess any ‘antibacterial activity’ whatsoever. In
fact, out of 12,000 sulfonylureas have been synthesized and clinically screened, and
approximately 10 compounds are being used currently across the globe for lowering
blood-sugar levels significantly and safely. The sulfonylureas may be represented by the
following s

Salient Features: The salient features of the ‘sulfonylureas’ are as given below :
(1) These are urea derivatives having an arylsulfonyl moiety in the 1 position and
an aliphatic function at the 3-position.
(2) The aliphatic moiety, R’, essentially confers lipophilic characteristic properties
to the newer drug molecule.
(3) Optimal therapeutic activity often results when R’ comprises of 3 to 6 carbon
atoms, as in acetohexamide, chlorpropamide and tolbutamide.
(4) Aryl functional moieties at R’ invariably give rise to toxic compounds.
(5) The R moiety strategically positioned on the ‘aromatic ring’ is primarily
responsible for the duration of action of the compound.

5.1.1.1 SAR of Sulfonylureas

 Certain substituents when placed at para position in benzene ring tend to
potentiate the activity, e.g. halogens, amino, acetyl, methyl, methylthio and
trifluoromethyl groups.

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 The size of terminal nitrogen along with its aliphatic subsituent R, determines
lipophilic properties of the molecules. Optimum activity results when R
consists of 3 to 6 carbon atoms.
 The nature of para subsituents in benzene ring (-x-) appears to govern the
duration of action of the compound.
 Aliphatic subsituents (R) at the terminal nitrogen may also be replaced by an
alicyclic and hetrocyclic ring.
 hypoglycemic activity can be related to the nature of sulfonyl grouping.
Replacement of a metabolically easily oxidize group, like a CH3 group by a less
readily oxidize chlorine was used to transform the short actingtolbutamide into long acting
chlorpropamide, with a half life six fold greater than its parent.
However, these agents are now divided into two sub-groups, namely:
(a) 1st generation sulfonylureas
(b) 2nd generation sulfonylureas

These two aforesaid classes of sulfonylureas will be further separated by:

 First-generation agents
o tolbutamide (Orinase)
o acetohexamide (Dymelor)
o tolazamide (Tolinase)
o chlorpropamide (Diabinese)
 Second-generation agents
o glipizide (Glucotrol)
o glyburide (Diabeta, Micronase, Glynase)
o glimepiride (Amaryl)
o gliclazide (Diamicron)

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 Tolbutamide

Structure

Systemic (IUPAC) Name

N-[(butylamino)carbonyl]-4-methylbenzenesulfonamide

Chemical data

FORMULA C12H18N2O3S
MOLECULAR MASS 270.35 g/mol

Pharmacokinetic data

METABOLISM Hepatic (CYP2C19-mediated)

PROTEIN BINDING 96 %
HALF LIFE 4.5 to 6.5 hours
EXECRETION Renal

Tolbutamide is a first generation potassium channel blocker, sulfonylurea oral

hypoglycemic drug sold under the brand name Orinase. This drug may be used in the
management of type II diabetes if diet alone is not effective. Tolbutamide stimulates the
secretion of insulin by the pancreas. Since the pancreas must synthesize insulin in order for
this drug to work, it is not effective in the management of type I diabetes. It is not
routinely used due to a higher incidence of adverse effects compared to newer second
generation sulfonylureas, such as glyburide.

 Mechanism of Action
The drug usually follows the major route of breakdown ultimately leading to the
formation of butylamine and p-toluene sulphonamide respectively. Importantly, the
observed hypoglycemia induced by rather higher doses of the drug is mostly not as severe
and acute as can be induced by insulin; and, therefore, the chances of severe hypoglycemic
reactions is quite lower with tolbutamide ; however, one may observe acute refractory
hypoglycemia occasionally does take place. In other words, refractoriness to it often
develops.

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 Side Effects
1. Hypoglycemia
2. Weight gain
3. Hypersensitivity- Cross-allergicity with sulfonamide
4. Drug Interactions (especially first generation drugs): Increase Hypoglycemia with
cimetidine, Insulin, salicylates, sulfonamides.

 Synthesis of Tolbutamide

Procedure
First of all toluene is treated with chlorosulfonic acid to yield p-toluenesulphonyl
chloride, which on treatment with ammonia gives rise to the formation of p-
toluenesulphonamide. The resulting product on condensation with ethyl chloroformate in
the presence of pyridine produces N-p-toluenesulphonyl carbamate with the loss of a mole
of HCl. Further aminolysis of this product with butyl amine using ethylene glycol
monomethyl ether as a reaction medium loses a mole of ethanol and yields tolbutamide. It
is mostly beneficial in the treatment of selected cases of non-insulin-dependent diabetes
melitus (NIDDM). Interestingly, only such patients having some residual functional islet
β-cells which may be stimulated by this drug shall afford a positive response. Therefore, it

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is quite obvious that such subjects who essentially need more than 40 Units of insulin per
day normally will not respond to this drug.

 Acetohexamide

Structure

Systemic (IUPAC) Name

4-acetyl-N-(cyclohexylcarbamoyl)benzenesulfonamide
Chemical data
FORMULA C15H20N2O4S
MOLECULAR MASS 324.395 g/mol
PROTEIN BINDING 90 %

It lowers the blood-sugar level particularly by causing stimulation for the release of
endogenous insulin.

 Mechanism of Action
The drug gets metabolized in the liver solely to a reduced entity, the corresponding
α-hydroxymethyl structural analogue, which is present predominantly in humans, shares
the prime responsibility for the ensuing hypoglycemic activity.

 Synthesis of Acetohexamide

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 SAR of Acetohexamide
It is found to be an intermediate between ‘tolbutamide’ and ‘chlorpropamide’ i.e.,
in the former the cyclohexyl ring is replaced by butyl moiety and p-acetyl group with
methyl group ; while in the latter the cyclohexyl group is replaced by propyl moiety and
the p-acetyl function with chloro moiety. Acetohexamide is metabolized in the liver to a
reduced from, the α-hydroxyethyl derivative. This metabolite, the main one in human,
possesses hypoglycemic activity. Acetohexamide is intermediate between tolbutamide and
chlorpropamide in potency and duration of effect on blood sugar level.

 Tolazamide

Structure

Systemic (IUPAC) Name

N-[(azepan-1-ylamino)carbonyl]-4-methylbenzenesulfonamide
Chemical data
FORMULA C14H21N3O3S
MOLECULAR MASS 311.401 g/mol
Pharmacokinetic data
HALF LIFE 7 hours
EXECRETION Renal (85%) and fecal (7%)

 Mechanism of Action

Based on the radiactive studies it has been observed that nearly 85% of an oral
dose usually appears in the urine as its corresponding metabolites which were certainly
more water-soluble than the parent tolazamide itself.

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 Synthesis of Tolazamide

 Chlorpropamide

Structure

Systemic (IUPAC) Name

1-[(p-Chlorophenyl)-Sulphonyl]-3-propyl urea
Chemical data
FORMULA C10H13ClN2O3S
MOLECULAR MASS 276.74 g/mol
HALF LIFE 36 hours

Chlorpropamide is a drug in the sulphonylurea class used to treat type 2 diabetes

mellitus. It is a long-acting sulphonylurea. It has more side effects than other
sulphonylureas and its use is no longer recommended.

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 Synthesis of Chlorpropamide

Procedure
The interaction between p-chlorobenzenesulphonamide and phenyl isocyanate in
equimolar concentrations under the influence of heat undergoes addition reaction to yield
the desired official compound.
The therapeutic application of this drug is limited to such subjects having a history
of table, mild to mderately severe diabetes melitus who still retain residual pancreatic β-
cell function to a certain extent.

 Mechanism of Action
The drug is found to be more resistant to conversion to its corresponding inactive
metabolites than is ‘tolbutamide’; and, therefore, it exhibits a much longer duration of
action. It has also been reported that almost 50% of the drug gets usually excreted as
metabolites, with the principal one being hydroxylated at the C-2 position of the propyl-
side chain.

 Glipizide

STRUCTURE

Systemic (IUPAC) Name

N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-5- methylpyrazine-2-carboxamide
Chemical data
FORMULA C21H27N5O4S
MOLECULAR MASS 445.536 g/mol
Pharmacokinetic data

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BIOAVAIBILITY 100% (regular formulation),90% (extended release)

PROTEIN BINDING 98 -99 %
METABOLISM Hepatic hydroxylation
HALF LIFE 2 to 4 hr
EXECRETION Renal and fecal
ROUTE Oral

Glipizide is an oral medium-to-long acting anti-diabetic drug from the sulfonylurea

class. It is classified as a second generation sulfonylurea, which means that it undergoes
enterohepatic circulation. The structure on the R2 group is a much larger cyclo or aromatic
group compared to the 1st generation sulfonylureas. This leads to a once a day dosing that
is much less than the first generation, about 100 fold.

 Mechanism of Action
The primary hypoglycemic action of this drug is caused due to the fact that it
upregulates the insulin receptors in the periphery. It is also believed that it does not exert a
direct effect on glucagon secretion. The drug gets metabolized via oxidation of the
cyclohexane ring to the corresponding p-hydroxy and m-hydroxy metabolites. Besides, a
‘minor metabolite’ which occurs invariably essentially involves the N-acetyl structural
analogue that eventually results, from the acetylation of the primary amine caused due to
the hydrolysis of the amide system exclusively by amidase enzymes.

 Synthesis of Glipizide

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Procedure
Glipizide may be prepared by the condensation of 4-[2-(5-methyl-2-pyrazine-
carboxamido)-ethyl] benzenesulphonamide with cyclohexylisocyanate in equimolar
proportions. It is employed for the treatment of Type 2 diabetes mellitus which is found to
be 100 folds more potent than tolbutamide in evoking the pancreatic secretion of insulin. It
essentially differs from other oral hypoglycemic drugs wherein the ensuing tolerance to
this specific action evidently does not take place.
Note : The drug enjoys two special status, namely:
(a) Treatment of non-insulin dependent diabetes mellitus (NIDDM) since it is
effective in most patients who particularly show resistance to all other hypoglycemic drugs
;
(b) Differs from other oral hypoglycemic drug because it is found to be more
effective during eating than during fasting.

 Gliclazide

Structure

Systemic (IUPAC) Name

N-(hexahydrocyclopenta[c]pyrrol-2(1H)-ylcarbamoyl)-4-methylbenzenesulfonamide
Chemical data
FORMULA C15H21N3O3S
MOLECULAR MASS 323.412 g/mol

Gliclazide is an oral hypoglycemic (anti-diabetic drug) and is classified as a

sulfonylurea.

 SAR of Gliclazide
Gliclazide is very similar to tolbutamide, with the exception of the bicyclic
hetrocyclic ring found in gliclazide. The pyrrolidine increases its lipophilicity over that of
tolbutamide, which increases its half life. Even so, the p-methyl is susceptible to the same
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oxidative metabolic fate as observed for tolbutamide, namely, it will be metabolized to a

carboxylic acid.

 Synthesis of Gliclazide

 Glimepiride

Structure

Systemic (IUPAC) Name

3-ethyl-4-methyl-N-(4-[N-((1r,4r)-4-methylcyclohexylcarbamoyl)sulfamoyl]phenethyl)-2-oxo-2,5-dihydro-
1H-pyrrole-1-carboxamide
Chemical data
FORMULA C24H34N4O5S
MOLECULAR MASS 490.617 g/mol
Pharmacokinetic data
PROTEIN BINDING >99.5%
HALF LIFE 5 hours
EXECRETION Urine and Fecal
ROUTES Oral

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 Mechanism of Action
The drug is found to be metabolized primarily through oxidation of the alkyl side
chain attached to the pyrrolidine nucleus via a minor metabolic path that essentially
involves acetylation of the amine function.

 Synthesis of Glimepiride

 SAR of Glimepiride
The only major distinct difference between this drug and glipizide is that the
former contains a five-membered ‘pyrrolidine ring’ whereas the latter contains a six-
membered ‘pyrazine ring’. It is metabolise primarily through oxidation of the alkyl side
chain of the pyrrolidine, with a minor metabolic route involving acetylation of the amine.

 Glibenclamide

Structure

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Systemic (IUPAC) Name

5-chloro-N-(4-[N-(cyclohexylcarbamoyl)sulfamoyl]phenethyl)-2-methoxybenzamide
Chemical data
FORMULA C23H28ClN3O5S
MOLECULAR MASS 494.004 g/mol
Pharmacokinetic data
PROTEIN BINDING Extensive
METABOLISM Hepatic hydroxylation (CYP2C9-mediated)
HALF LIFE 1.5 to 5 hours
EXECRETION Renal and Biliary
ROUTES Oral

Glibenclamide (INN), also known as glyburide (USAN), is an anti-diabetic drug in

a class of medications known as sulfonylureas. It is mostly used for Type 2 diabetes
melitus. It is found to be almost 200 times as potent as tolbutamide in evoking the release
of insulin from the pancreatic islets. However, it exerts a rather more effective agent in
causing suppression of fasting than postprandial hyperglycemia.

 Synthesis of Glibenclamide

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 SAR of Glyburide
The SAR of Glyburide and Glypizzide are discussed below :

DRUG pKa Potency Compared to Tolbutamide

Glipizide 5.9 100 times more potent
Glyburide 5.3 200 times more potent

Obviously the presence of ‘R’ in glyburide potentiates the hypoglycemic activity

200 times, whereas the heterocylic nucleus in glipizide potentiates 100 times in
comparison to tolbutamide. It is 2nd generation oral hypoglycemic agent. The drug has a
half life elimination of 10 hours, but its hypoglycemic effects remains for up to 24 hours.

 Mechanism of Action
The drug gets absorbed upto 90% when administered orally from an empty
stomach. About 97% gets bound to plasma albumin in the form of a weak-acid anion; and
therefore, is found to be more susceptible to displacement by a host of weakly acidic drug
substances. Elimination is mostly afforded by ‘hepatic metabolism’. The half-life ranges
between 1.5 to 5 hours, and the duration of action lasts upto 24 hours.

5.1.2 Meglitinide
Metaglinides are nothing but non sulphonylurea oral hypoglucemic agents
normally employed in the control and management of type 2 diabetes (i.e, non-insulin-
dependent diabetes mellitus, NIDDM). Interestingly, these agents have a tendency to show
up a quick and rapid onset and a short duration of action. Just like the ‘sulphonylureas’,
they also exert their action by inducing insulinrelease from the prevailing functional

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pancreatic β-cells. Importantly the mechanism of action of the ‘metaglinides’ is observed

to differ from that of the ‘sulphonylureas’.
In fact, the mechanism of action could be explained as under:
(a) Through binding to the particular receptors in the β-cells membrane that
ultimately lead to the closure of ATP-dependent K+ channels, and
(b) K+ channel blockade affords depolarizes the β-cell membrane, which iN turn
gives rise to Ca2+ influx, enhanced intracellular Ca2+, and finally stimulation of insulin
secretion.
Based on the altogether different mechanism of action from the two aforesaid
‘sulphonylureas’ there exist two distinct, major and spectacular existing differences
between these two apparently similar categories of ‘drug substances’, namely :
(i) Metaglinides usually produe substantially faster insulin production in comparison
to the ‘sulphonyl ureas’, and, therefore, these could be administered in-between meals by
virtue of the fact that under these conditions pancreas would produce insulin in a relatively
much shorter duration, and
(ii) Metaglinides do not exert a prolonged duration of action as those exhibited by the
‘sulphonylureas’. Its effect lasts for less than 1 hour whereas sulphonylureas continue to
cause insulin generation for several hours.

 Repaglinide

Structure

Systemic (IUPAC) Name

(S)-(+)-2-ethoxy-4-[2-(3-methyl-1-[2-(piperidin-1-yl)phenyl]butylamino)-2-oxoethyl]benzoic acid
Chemical data
FORMULA C27H36N2O4
MOLECULAR MASS 452.586 g/mol
Pharmacokinetic data
BIOAVAIBILITY 56 % (oral)
PROTEIN BINDING >98 %

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METABOLISM Hepatic oxidation and glucuronidation (CYP3A4-

mediated)
HALF LIFE 1 hr
EXECRETION Fecal (90%) and renal (8%)
ROUTES Oral

It is used in the control and management of Type-2 diabetes mellitus. It must be

taken along with meals.

 Mechanism of Action
The drug is found to exert its action by stimulating insulin secretion by binding to
and inhibiting the ATP-dependent K+ channels in the β-cell membrane, resulting
ultimately
in an opening of Ca+2 channels. It gets absorbed more or less rapidly and completely from
the GI tract; and also is exhaustively metabolized in the liver by two biochemical
phenomena, such as:
(a) Glucuronidation; and
(b) Oxidative biotransformation. Besides, it has been established that the hepatic
cytochrome P-450 system 3A4 is predominantly involved in the ultimate metabolism of
repaglinide.

 SAR of Repaglinide
Repaglinide represents a new class of nonsulfonylurea oral hypoglycemic agent.
With a fast onset and short duration of action, the medication should be taken with meals.
It is oxidized by CYP 3A4, and the carboxylic acid may be conjugated to inactive
compounds. Less than 0.2 % is excreated unchanged by kidney, which may be an
adventage for elderly patients who are renally impaired.

 Side effects
The most common side effects involves hypoglycemia, resulting in headache, cold
sweats, anxity, and changes in mental state.

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 Nateglinide

Structure

Systemic (IUPAC) Name

(R)-2-(4-isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid
Chemical data
FORMULA C19H27NO3
MOLECULAR MASS 317.423 g/mol
Pharmacokinetic data
PROTEIN BINDING 98 %
HALF LIFE 1.5 hr

Nateglinide (INN, trade name Starlix) is a drug for the treatment of type 2 diabetes.
Nateglinide was developed by the Swiss pharmaceutical company Novartis.
Nateglinide belongs to the meglitinide class of blood glucose-lowering drugs.

 Dosage
Nateglinide is delivered in 60mg & 120mg tablet form.

5.2 GLP-I analogs

5.2.1 Glucagon-like peptide-1 hormons

It is the incretin hormone acting via GLP-1 receptor (a G-protein coupled receptor).
When blood glucose levels are high this hormone stimulates insulin secretion and
biosynthesis and inhibits glucagon release leading to reduce hepatic glucose output. In
addition it serves as an “ileal brake”, slowing gastric emptying and reducing appetite.
GLP-1 has a no. of effects on regulation of β-cell mass: stimulation of replication and
growth and inhibition of apoptosis of existing β-cells and neogenesis of new β-cells from

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precursors. Thus, GLP-1 therapy for the treatment of type 2 diabetes is an area of active
research.
There are two sub-classes of GLP-1 in clinical development .One is natural GLP-1
and the other is exendin-4, a peptide agonist isolated from the venom of lizard and is more
potent than natural GLP-1.
Exenatide (AC2993) is a peptide consist of 39 amino acid approved recently
developed by Lilly and Amylin & used for treatment of diabetes. Liraglutide (NN2211), is
under phase ΙΙ clinical trial by Novo Nordisk, CJC1131 is under phase I / ΙΙ clinical trial
by Conjuchem, ZP10 is under phase I / ΙΙ clinical trial by Zealand.
Glucagon-like peptide-1 analogs are a new class of drug for treatment of type 2
diabetes. One of their advantages is that they have a lower risk of causing hypoglycemia.

 Exenatide

Structure

Chemical data
FORMULA C184H282N50O60S
Pharmacokinetic data
METABOLISM Proteolysis
HALF LIFE 2.4 hr
EXECRETION renal/proteolysis
ROUTES subcutaneous injection

Exenatide (INN, marketed as Byetta) is one of a new class of medications (incretin

mimetics) approved (Apr 2005) for the treatment of diabetes mellitus type 2. (It is not
approved for use in diabetes mellitus type 1). It is manufactured by Eli Lilly and
Company.
Exenatide is administered as a subcutaneous injection (under the skin) of the
abdomen, thigh, or arm, 30 to 60 minutes before the first and last meal of the day.

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 Albiglutide
Albiglutide is a drug under investigation by GlaxoSmithKline for treatment of type
2 diabetes. It is a dipeptidyl peptidase-4-resistant glucagon-like peptide-1 dimer fused to
human albumin. It has a half life of 6 to 7 days (longer than exenatide or liraglutide).

5.3 Protein Tyrosin Phosphate 1β inhibitors

Phosphatases are the enzyme which remove phosphate group from the substrate
process known as dephosphorylation. Protein tyrosine phosphatase (PTP) is the enzyme
acts by dephosphorylation of the tyrosine kinase.Tyrosine phosphorylation of proteins is a
fundamental mechanism for the control of cell growth and differentiation. It is reversible
and governed by the opposing activities of protein tyrosine kinases (PTKs), which catalyse
phosphorylation and protein tyrosine phosphatases (PTPs), which are responsible for
dephosphorylation. Defective or inappropriate operation of these network leads to aberrant
tyrosine phosphorylation, contributing to the development of many diseases like cancer
and diabetes. Phosphorylation is reversible. PTPs are the enzymes play an important role
in cellular signaling. PTPs are the enzymes not only function as negatively but also
positively i.e. they are not only the cause of a disease they are used in the treatment of
diseases.
PTPs can be divided into three major subfamilies – tyrosine-specific, dualspecific
and low molecular weight phosphatases. The dual-specific phosphatase utilizes the protein
substrate that contains pTyr as well as pSer and pThr. Several PTPs have been implicated
as negative regulators of the insulin signalling pathway; these include TC-PTP, SHP-2,
PTEN, PTP-LAR, and PTP-1B. PTP-1β is a cytosolic phosphates consisting of a single
catalytic domain. PTPs are divided into 2 classes:
a) Non transmembrane.
b) Transmembrane type or Receptor type

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Fig.5.1 Classification of PTP

5.3.1 Protein tyrosine phosphatase-1β ( PTP-1β)

PTB-1β a founding member of PTPase with 435 amino acid residues was first
purified from human placental tissue in 1988 and first crystallized in 1994. PTP-1β
belongs to non transmembrane class of enzymes. PTP-1β is an abundant enzyme
expressed in nearly all tissues where it is localized primarily on intracellular membranes
by a C-terminal sequence. PTP-1β acts as negative regulator of insulin signalling. It acts
by causing dephosphorylation of insulin receptor. It also causes negative regulation of
insulin signaling. It is involved in type-2 diabetes & obesity. It has been shown mice
lacking PTP-1β show enhance insulin activity, resistant to development of obesity. In
vitro, it is a non-specific PTP and dephosphorylates a wide variety of substrates. In vivo, it
is involved in down regulation of insulin signalling by dephosphorylation of specific
phosphotyrosine residues on the insulin receptor. Administration of PTP-1β antisense
oligonucleotides to diabetic obese mice reduces plasma glucose and brings insulin level to
normal. PTP-1β knockout mice have shown increased insulin sensitivity and decreased
weight gain after a high fat diet. All these evidences help to validate PTP-1β as a
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keynegative regulator of insulin signal transduction and a potential therapeutic target in the
treatment of NIDDM and obesity.

5.3.2 Role of PTP-1β in Insulin & Leptin signaling

Binding of insulin to insulin receptor α-subunit induces conformational change in β-

subunit which in turns activates insulin receptor tyrosine kinase which causes
phosphorylation of insulin receptor substrate which is responsible for down stream
signaling through recruitment of appropriate signal transducers which is responsible for
various effect exerted by insulin (Fig.5.2). It has been shown recently that PTP-1β
negatively regulates leptin receptor signaling in a murine neuronal subline.PTP-1β acts to
block leptin signaling by dephosphorylating jleptinanus kinase (jak)- 2. Leptin is a key
adipokine regulating food intake & energy expenditure. It is likely that the resistance to
diet induced obesity is due, atleast in part, to increased leptin ssenstivity in the PTP-1β
knockout mice.

Fig.5.2: Role of PTP-1B in insulin signaling

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5.3.3 Structure of PTP-1β

Red:Catalytic site ,(His214-Arg221); Blue: second aryl phosphate binding site

Yellow :( Tyr46-Arg47-Asp48) , Magenta: (Asp181 and Phe182)

Fig.5.3: Structure of PTP-1β showing main sites

The active site of PTP-1β contains a common structural motif His–Cys–Ser–Ala–

Gly–Ile–Gly–Arg, forming a rigid, cradle like structure that coordinates to the aryl
phosphate moiety of the substrate. It contains an active site nucleophile, Cys 215. It also
contain second aryl phosphate binding site. In the above structure, red is main catalytic
active site which is from His 214 –Arg 221, in the blue is contain second aryl phosphate
binding site, in the yellow is YRD loop which play an important role in substrate binding,
and in the magenta is Wpd loop which contain Asp181 & Phe 182 which is full of water
and responsible for hydrogen bonding interactions. The dephosphorylation of tyrosine
takes place via two steps. In the first step there is a nucleophilic attack on the substrate
phosphate by the sulphur atom of Cys, coupled with protonation of tyrosyl leaving group
by Asp181 acting as a general acid.
This leads to the formation of cysteinyl phosphate intermediate. The second step
mediated by Glu262 and Asp181, leads to the hydrolysis of catalytic intermediate and
release of phosphate.

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PTP-1β has been closely structurally correlated with other members of PTP family
especially TC-PTP. PTP-1β causes simultaneous dephosphorylation of phosphorylated
1162 & 1163 residue of insulin receptor thus causing inhibition of insulin signalling while
other PTP s does not causes simultaneous dephosphorylation thus has important role in
insulin signaling.

Fig.5.4: Structure of PTP-1β showing simultaneous dephosphorylation of insulin receptor

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5.3.4 PTP-1β Inhibitors

Phosphatase LAR, CD45, SHP-2, cdc25c and T-cell PTP (TCPTP) share 50–80%
homology in the catalytic domain with PTP-1β, which presents a challenging task of
achieving selectivity, especially over TCPTP. Thus it was necessary for the inhibitors to
interact with the regions outside the catalytic site in order to be selective. A non-catalytic
phosphotyrosine-binding site was identified, which seems to be ideal since it is close to the
catalytic site and is less homologous between the PTP-1β and TCPTP when the amino acid
sequences were compared. Hence targeting both the sites simultaneously may show good
activity and selectivity against PTP-1 β. PTPase have been inhibited experimentally using
a variety of mechanisms and chemical entities. PTPase can be inhibited by chemical
inactivation of the active site cysteine residue common to all members of the family. This
inactivation may occur via an oxidative mechanism initiated by reactive species such as
pervanadate and peroxides e.g. Most of early PTP-1β inhibitors are phosphate-based and
the most studied phosphate-based PTP-1β inhibitors are difluorophosphonates e.g. This
difluorophosphonate group was introduced as a nonhydrolyzable phosphotyrosine mimetic
in 1992 by Burke and coworkers.2-(Oxalylamino)-benzoic acid (OBA) e.g. was identified
as a general, reversible and competitive inhibitor of severalPTPase using a scintillation
proximity-based high throughput screening by workers at Novo Nordisk.
High-throughput screening has allowed the identification of several more PTP-1β
inhibitor classes having various mechanisms of action. Pyridazine derivatives such as were
identified at Biovitrum potencies in a low micromolar range (5.6μM) and over 20 fold
selectivity over TC-PTP. Hydroxyphenylazole derivatives such as with IC50 value in the
micromolar range, were claimed by Japan Tobacco. A series of azolidinediones e.g., and
phenoxyacetic acid based PTP1β inhibitors e.g., have been reported by American Home
Products. More recently a group at Hoffmann-LaRoche described novel
pyrimidotriazinepiperidine analogues e.g., with oral glucose lowering effect in ob/ob mice.
The inhibition of PTP1β by this class of compounds presumably involves the oxidation of
the active site. Alpha-bromoacetophenone derivatives act as potent PTP inhibitors by
covalently alkylating the conserved catalytic cysteine in the PTP active site.
Derivatization of the phenyl ring with a tripeptide Gly–Glu–Glu29 resulted in potent,
selective inhibitors against PTP-1β cysteine of PTP1β to the corresponding sulfenic acid.

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Despite good biological target validation, designing PTP-1β inhibitors as oral agent
is challenging because of the highly charged nature of the catalytic domain of the target.
Furthermore the development of selective, potent and bioavailable inhibitors of PTP-1β
will be a formidable challenge although some of the groundwork has now been laid out.

5.4 Dipeptidyl peptidase-4 inhibitor

Inhibitors of Dipeptidyl peptidase 4 also called as DPP-4 inhibitors, are a class of

oral hypoglycemics that block DPP-4. They can be used to treat diabetes mellitus type 2.
The first agent of the class - sitagliptin - was approved by the FDA in 2006.
Sitagliptin entered the Australian drug market in late 2007 for the treatment of difficult-to-
control diabetes mellitus type 2.
Their mechanism of action is thought to result from increased Incretin levels (GLP-
1 and GIP), which inhibit glucagon release, the effect of which, in turn, decreases blood
glucose, but, more significant, increases insulin secretion and decreases gastric emptying.

Figure No.5.5 Dipeptidyl peptidase-4 inhibitor

The role of DPP-4, GLP-1 in glucose homeostasis. Following meal ingestion, the
incretin hormones, intact (active) GLP-1 and GIP, released from gut endocrine cells and

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function to lower blood glucose levels by stimulating glucose-dependent insulin release

from pancreatic β-cells (GLP-1 and GIP) and suppressing glucose-dependent glucagon
release from pancreatic α-cells (GLP-1). However, once released into the circulation,
incretin hormones are rapidly inactivated and degraded by plasma protease enzyme DPP-
4. DPP-4 inhibitors like sitagliptin inhibit breakdown of incretin hormones, thereby
increasing active GLP-1 and GIP levels and promoting fasting and postprandial glycemic
control.

5.4.1 Examples
Drugs belonging to this class are:
 sitagliptin (FDA approved 2006, marketed by Merck & Co. under the trade name
Januvia),
 vildagliptin (marketed in the EU by Novartis under the trade name Galvus),
 Saxagliptin (being developed by Bristol-Myers Squibb, AstraZeneca and Otsuka
Pharmaceutical Co.),
 linagliptin (being developed by Boehringer Ingelheim),
 Alogliptin (developed by Takeda Pharmaceutical Company, whose FDA
application for the product is currently suspended as of June 2009).
Berberine, the common herbal dietery supplement, too inhibits dipeptidyl peptidase-4,
which at least partly explains its anti-hyperglycemic activities.

5.4.2 Possible cancer risk

Although extensive long-term, pre-clinical studies of the major DPP-4 inhibitors
has failed to show any evidence of potential to cause tumors in laboratory animals, there
was one in-vitro (i.e., test tube) study that has raised some questions. In theory, DPP-4
inhibitors may allow some cancers to progress, since DPP-4 appears to work as a
suppressor in the development of cancer and tumours.

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 Alogliptin

Structure

Systemic (IUPAC) Name

2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-
3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile
Chemical data
FORMULA C18H21N5O2
MOLECULAR MASS 339.39 g/mol
ROUTES Oral

Alogliptin (codenamed SYR-322) is an investigational anti-diabetic drug in the

DPP-4 inhibitor class, being developed by Takeda Pharmaceutical Company. Takeda has
submitted a New Drug Application for alogliptin to the U.S. Food and Drug
Administration, after positive results from Phase III clinical trials.FDA submission
suspended or withdrawn June 2009 needing more data.

 Linagliptin

Structure

Systemic (IUPAC) Name

8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3- methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-
dihydro-1H-purine-2,6-dione
Chemical data
FORMULA C25H26N8O2
MOLECULAR MASS 472.54 g/mol
ROUTES Oral

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Linagliptin (BI-1356, expected trade name Ondero) is a DPP-4 inhibitor developed

by Boehringer Ingelheim undergoing research for type II diabetes. It is currently in a Phase
III clinical trial.

 Saxagliptin

Structure

Systemic (IUPAC) Name

(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)
acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile
Chemical data
FORMULA C18H25N3O2
MOLECULAR MASS 315.41 g/mol

Saxagliptin (rINN), previously identified as BMS-477118, is a new oral

hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor
class of drugs. It was developed by Bristol-Myers Squibb. In June 2008, it was announced
that Onglyza would be the trade name under which saxagliptin will be marketed. The FDA
approved Onglyza on July 31, 2009. Dipeptidyl peptidase-4's role in blood glucose
regulation is thought to be through degradation of GIP and the degradation of GLP-1.
Bristol-Myers Squibb announced on 27 December 2006 that Otsuka
Pharmaceutical Co. has been granted exclusive rights to develop and commercialize the
compound in Japan. Under the licensing agreement, Otsuka will be responsible for all
development costs, but Bristol-Myers Squibb retains rights to co-promote saxagliptin with
Otsuka in Japan. Further, on 11 January 2007 it was announced that Bristol-Myers Squibb
and AstraZeneca would work together to complete development of the drug and in
subsequent marketing.

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 Sitagliptin

Structure

Systemic (IUPAC) Name

(R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-
trifluorophenyl)butan-2-amine
Chemical data
FORMULA C16H15F6N5O
MOLECULAR MASS 407.314 g/mol
Pharmacokinetic data
BIOAVAIBILITY 87 %
PROTEIN BINDING 38 %
METABOLISM Hepatic (CYP3A4- and CYP2C8-mediated)
HALF LIFE 8 to 14 hour
EXECRETION Renal (80%)
ROUTES Oral

Sitagliptin (INN; previously identified as MK-0431, trade name Januvia) is an oral

antihyperglycemic (anti-diabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor
class, Sitagliptin being the only second generation DPP-4 inhibitor currently available in
the USA. This enzyme-inhibiting drug is used either alone or in combination with other
oral antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment of
diabetes mellitus type 2. The benefit of this medicine is its lower side-effects (e.g., less
hypoglycemia, less weight gain) in the control of blood glucose values. Exenatide (Byetta)
also works by its effect on the incretin system.

 Mechanism of Action
Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-
4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones that
are released in response to a meal. By preventing GLP-1 and GIP inactivation, GLP-1 and

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GIP are able to potentiate the secretion of insulin and suppress the release of glucagon by
the pancreas. This drives blood glucose levels towards normal. As the blood glucose level
approaches normal, the amounts of insulin released and glucagon suppressed diminishes
thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia)
which is seen with some other oral hypoglycemic agents.

 Vildagliptin
Systemic (IUPAC) Name
(S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile
Chemical data
FORMULA C17H25N3O2
MOLECULAR MASS 303.399 g/mol
SYNONYMS (2S)-1-{2-[(3-hydroxy-1-
adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile
Pharmacokinetic data
BIOAVAIBILITY 85 %
PROTEIN BINDING 9.3 %
METABOLISM Mainly hydrolysis to inactive metabolite; CYP450
not appreciably involved
HALF LIFE 2 to 3 hr
EXECRETION Renal
ROUTES Oral

Vildagliptin (previously identified as LAF237, trade name Galvus) is a new oral

anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4)
inhibitor class of drugs. Vildagliptin inhibits the inactivation of GLP-1 and GIP by DPP-4,
allowing GLP-1 and GIP to potentiate the secretion of insulin in the beta cells and
suppress glucagon release by the alpha cells of the islets of Langerhans in the pancreas.
Vildagliptin has been shown to reduce hyperglycemia in type 2 diabetes mellitus.
Novartis has since withdrawn its intent to submit vildagliptin to the FDA, as of
July 2008. The Food and Drug Administration had demanded additional clinical data
before it could approve vildagliptin including extra evidence that skin lesions and kidney
impairment seen during an early study on animals have not occurred in human trials.

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6. Sensitizers

6.1 Biguanide

Structure

Systemic (IUPAC) Name

Diguanide, 2-carbamimidoylguanidine
Chemical data
FORMULA C2H7N5
MOLECULAR MASS 101.11 g/mol

Biguanide can refer to a molecule, or to a class of drugs based upon this molecule.
Biguanides can function as oral antihyperglycemic drugs used for diabetes mellitus or
prediabetes treatment. They are also used as antimalarial drugs. The disinfectant
polyaminopropyl biguanide (PAPB) features biguanide functional groups.

6.1.2 Examples of biguanides:

 Metformin - widely used in treatment of diabetes mellitus type 2
 Phenformin - withdrawn from the market in most countries due to toxic effects
 Buformin - withdrawn from the market due to toxic effects

6.1.3 Mechanism of action

The mechanism of action of biguanides is not fully understood. However, in
hyperinsulinemia, biguanides can lower fasting levels of insulin in plasma. Their
therapeutic uses derive from their tendency to reduce gluconeogenesis in the liver, and, as
a result, reduce the level of glucose in the blood. Biguanides also tend to make the cells of
the body more willing to absorb glucose already present in the blood stream, and there
again reducing the level of glucose in the plasma.

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 Metformin

Structure

Systemic (IUPAC) Name

N,N-dimethylimidodicarbonimidic diamide
Chemical data
FORMULA C4H11N5
MOLECULAR MASS 129.164 g/mol (free)
165.63 g/mol (HCl)
SYNONYMS 1,1-dimethylbiguanide
Pharmacokinetic data
BIOAVAIBILITY 50 to 60% under fasting conditions
METABOLISM None
HALF LIFE 6.2 hours
EXECRETION Active renal tubular excretion by OCT2
ROUTES Oral
It is used as an oral antihyperglycemic drug for the management of Type 2 diabetes
mellitus. It is invariably recommended either as monotherapy or as an adjunct to diet or
with a sulphonylurea (combination) to reduce blood-glucose levels.

 Mechanism of Action
The drug is found to lower both basal and postprandial glucose. Interestingly, its
mechanism of action is distinct from that of sulphonylureas and does not cause
hypoglycemia. However, it distinctly lowers hepatic glucose production, reduces intestinal
absorption of glucose, and ultimately improves insulin sensitivity by enhancing
appreciably peripheral glucose uptake and its subsequent utilization. The drug is mostly
eliminated unchanged in the urine, and fails to undergo hepatic metabolism.

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 Synthesis of Metformin

Procedure
Metformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide
hydrochloride) is an oral antihyperglycemic drug used in the management of diabetes. It is
usually prepared from the reaction between dimethylamine hydrochloride and dicyano
diamide at 120-140 oC in 4 hrs time with 69% yield. In designing ecofriendly synthesis of
the target molecule, the starting materials are made to react by modifying the reaction
conditions in such a way that the by-products and wastes are eliminated and also the use of
organic solvents is minimized.Thin layer chromatography (TLC) has been reported as a
tool for reaction optimization in microwave assisted synthesis. This method has been used
to modify a conventional procedure for an efficient synthesis of metformin hydrochloride
by simply spotting of the reaction mixture on a TLC plate and then subjecting it to
microwave irradiation.
 Formulations
Metformin is sold under several trade names, including Glucophage XR, Riomet,
Fortamet, Glumetza, Obimet, Dianben, Diabex, and Diaformin. Metformin IR (immediate
release) is available in 500 mg, 850 mg, and 1000 mg tablets, all now generic in the US.

 Buformin

Structure

Systemic (IUPAC) Name

N-butylimidocarbonimidic diamide

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Chemical data
FORMULA C6H15N5
MOLECULAR MASS 157.217 g/mol
Pharmacokinetic data
EXECRETION Renal
ROUTES Oral
LEGAL STATUS Withdrawn in most countries

Buformin is an anti-diabetic drug of the biguanide class, it is chemically related to

metformin, and phenformin. It was withdrawn from the market in most countries due to a
high risk of causing lactic acidosis. This drug is still used in some countries, such as
Romania and Spain. It is marketed by German pharmaceutical company Grünenthal.

 Phenformin

Structure

Systemic (IUPAC) Name

2-(N-phenethylcarbamimidoyl)guanidine
Chemical data
FORMULA C10H15N5
MOLECULAR MASS 205.26 g/mol
Phenformin is an anti-diabetic drug from the biguanide class. It was marketed as
DBI by Ciba-Geigy but was withdrawn from most markets in the late 1970s due to a high
risk of lactic acidosis, which was fatal in 50% of cases.

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6.2 Thiazolidinedione
The medication class of thiazolidinedione (also called glitazones) was introduced
in the late 1990s as an adjunctive therapy for diabetes mellitus (type 2) and related
diseases.

6.2.1 Mode of action

Thiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-
activated receptors), a group of receptor molecules inside the cell nucleus, specifically
PPARγ (gamma). The ligands for these receptors are free fatty acids (FFAs) and
eicosanoids. When activated, the receptor migrates to the DNA, activating transcription of
a number of specific genes.
Genes upregulated by PPARγ can be found in the main article on peroxisome
proliferator-activated receptors.
By activating PPARγ:
 Insulin resistance is decreased
 Adipocyte differentiation is modified
 VEGF-induced angiogenesis is inhibited
 Leptin levels decrease (leading to an increased appetite)
 Levels of certain interleukins (e.g. IL-6) fall
 Adiponectin levels rise

6.2.2 Synthesis of N-substituted 2, 4-thiazolidinediones from oxazolidinethiones

A novel reaction has been found between oxazolidinethione and bromoacetyl
bromide to afford N-substituted 2,4-thiazolidinediones through an intramolecular
nucleophilic substitution reaction. Interestingly a step of elimination was carried out in
trisubstituted oxazolidinethiones forming a double bond.

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6.2.3 Members of the class

The chemical structure of thiazolidinedione

Chemically, the members of this class are derivatives of the parent compound
thiazolidinedione, and include:
 Rosiglitazone (Avandia)
 Pioglitazone (Actos)
 Troglitazone (Rezulin), which was withdrawn from the market due to an increased
incidence of drug-induced hepatitis.

6.2.4 Uses
The only approved use of the thiazolidinediones is in diabetes mellitus type 2.
It is being investigated experimentally in polycystic ovary syndrome (PCOS), non-
alcoholic steatohepatitis (NASH), psoriasis, autism, and other conditions.
Several forms of lipodystrophy cause insulin resistance, which has responded
favorably to thiazolidinediones. There are some indications that thiazolidinediones provide
some degree of the protection against initial stages of the breast carcinoma development.

 Pioglitazone

STRUCTURE

Systemic (IUPAC) Name

(RS)-5-(4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl)thiazolidine-2,4-dione

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Chemical data
FORMULA C19H20N2O3S
MOLECULAR MASS 356.44 g/mol
Pharmacokinetic data
PROTEIN BINDING >99 %
METABOLISM liver (CYP2C8)
HALF LIFE 3–7 hours
EXECRETION In bile
ROUTES Oral

Pioglitazone is a prescription drug of the class thiazolidinedione (TZD) with

hypoglycemic (antihyperglycemic, antidiabetic) action. Pioglitazone is marketed as
trademarks Actos in the USA and UK, Glustin in Europe, Zactos in Mexico by Takeda
Pharmaceuticals & Piozer in Pakistan by Hilton Pharmaceuticals. Actos was the tenth-best
selling drug in the U.S. in 2008, with sales exceeding $2.4 billion.

 Side effects
Pioglitazone can cause fluid retention and peripheral edema. As a result, it may
precipitate congestive heart failure (which worsens with fluid overload in those at risk). It
may cause anemia. Mild weight gain is common due to increase in subcutaneous adipose
tissue. In studies, patients on pioglitazone had a slightly increased proportion of upper
respiratory tract infection, sinusitis, headache, myalgia and tooth problems.

 Rivoglitazone

Structure

Systemic (IUPAC) Name

(RS)-5-{4-[(6-methoxy-1-methyl-1H-benzimidazol-2-yl) methoxy]benzyl}-1,3-thiazolidine-2,4-dione
Chemical data
FORMULA C20H19N3O4S
MOLECULAR MASS 397.448 g/mol

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Rivoglitazone (INN) is a thiazolidinedione undergoing research for use in the

treatment of type 2 diabetes. It is being developed by Daiichi Sankyo Co.

 Rosiglitazone

STRUCTURE

Systemic (IUPAC) Name

(RS)-5-[4-(2-[methyl(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione
Chemical data
FORMULA C18H19N3O3S
MOLECULAR MASS 357.428 g/mol
Pharmacokinetic data
BIOAVAIBILITY 99 %
PROTEIN BINDING 99.8 %
METABOLISM Hepatic (CYP2C8-mediated)
HALF LIFE 3 – 4 hours
EXECRETION Renal (64%) and fecal (23%)
ROUTES Oral
Rosiglitazone is an anti-diabetic drug in the thiazolidinedione class of drugs. It is
marketed by the pharmaceutical company GlaxoSmithKline as a stand-alone drug
(Avandia) and in combination with metformin (Avandamet) or with glimepiride
(Avandaryl). Annual sales peaked at approx $2.5bn in 2006. The drug's patent expires in
2012.
Some reports have suggested that rosiglitazone is associated with a statistically
significant risk of heart attacks, but other reports have disagreed, and the controversy has
not been resolved. Concern about adverse effects has reduced the use of rosiglitazone
despite its important and sustained effects on glycemic control.

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 Side effects
Heart disease, Bone fractures, Eye damage, Hepatotoxicity

 Troglitazone

Structure

Systemic (IUPAC) Name

5-(4-[(6-hydroxy-2,5,7,8-tetramethylchroman-2-yl)methoxy]benzyl)thiazolidine-2,4-dione
Chemical data
FORMULA C24H27NO5S
MOLECULAR MASS 441.541 g/mol
HALF LIFE 16-34 hours

Troglitazone (Rezulin, Resulin or Romozin) is an anti-diabetic and

antiinflammatory drug, and a member of the drug class of the thiazolidinediones. It was
developed by Daiichi Sankyo Co.(Japan). It was introduced and manufactured by Parke-
Davis in the late 1990s but turned out to be associated with an idiosyncratic reaction
leading to drug-induced hepatitis. Evaluating FDA medical officer Dr. John Gueriguian
had disapproved it due to high liver toxicity. But the FDA stripped Gueriguian of his post
and discarded his report under successful corporate pressure to approve the drug.
It was withdrawn from the United Kingdom market (sailing by Glaxo) on
December 1997.after,from the USA market on 21 March 2000, and from the Japan
markets(introduced and manufactured by Sankyo.Co.) soon afterwards.

 Mode of action
Troglitazone, like the other thiazolidinediones (pioglitazone and rosiglitazone),
works by activating PPARs (peroxisome proliferator-activated receptors). Troglitazone is

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a ligand to both PPARα and - more strongly - PPARγ. Troglitazone also contains an α-
tocopheroyl moiety, potentially giving it vitamin E-like activity in addition to its PPAR
activation. It has been shown to reduce inflammation: troglitazone use was associated with
a decrease of nuclear factor kappa-B (NFκB) and a concomitant increase in its inhibitor
(IκB). NFκB is an important cellular transcription regulator for the immune response.

6.3 PPAR modulator41-45

Figure 6.1 PPAR α and γ pathways.

PPAR modulators are drugs which act upon the peroxisome proliferator-activated receptor.

6.3.1 PPAR α/γ dual agonist

These agents are shown to ameliorate the hyperglycemia and hyperlipidmia
associated with type 2 diabetes. In addition to their benefit on lipids the activation of
PPARα may mitigate the weight gain induced by PPARγ activation .So this dual agonist is
supposed to provide additive and possibly synergistic effects.
First literature report of a balanced PPAR α/γ dual agonist was KRP-297 (MK-
767), a TZD derivative that was reported to bind PPARα and PPARγ with an affinity of
approx.0.230 and 0.33 μM respectively and to trans activate PPARα and PPARγ with
potencies of 1.0 and 0.8 μM followed by phenylpropionic acid based PPAR α/γ dual

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agonists Tesaglitazar (AZ-242) by Astra Zeneca, reportedly in phase III clinical trial,
Ragaglitazar (DRF-2725) by Dr. Reddy’s Research foundation, reportedly completed
phase ΙΙ clinical trial but clinical development being terminated due to an incidence of
bladder tumors in rodents. LY-510925 is a result of collaborative effort of Ellily Lilly and
Ligand pharmaceuticals, Muraglitazar (BMS –298585) is disclosed by Cheng et al.

 Aleglitazar

Structure

Chemical data
FORMULA C24H23NO5S
MOLECULAR MASS 437.50812 gm/mol

Aleglitazar is a peroxisome proliferator-activated receptor agonist (hence a PPAR

modulator ) with affinity to PPARα and PPARγ, which is being developed by Hoffmann–
La Roche for the treatment of type II diabetes. It is currently in phase II clinical trials.

 Muraglitazar

Structure

Systemic (IUPAC) Name

N-[(4-methoxyphenoxy)carbonyl]-N-{4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)ethoxy]benzyl}glycine
Chemical data
FORMULA C29H28N2O7
MOLECULAR MASS 516.54 g/mol

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Muraglitazar (proposed tradename Pargluva) is a peroxisome proliferator-activated

receptor agonist with affinity to PPARα and PPARγ.
The drug had completed phase III clinical trials, however in May, 2006 Bristol-
Myers Squibb announced that it had discontinued further development.

 Tesaglitazar

Structure

Systemic (IUPAC) Name

(2S)-2-Ethoxy-3-[4-[2-(4-methylsulfonyloxyphenyl)ethoxy]phenyl]propanoic acid
Chemical data
FORMULA C20H24O7S
MOLECULAR MASS 408.46 gm/mol

Tesaglitazar is a peroxisome proliferator-activated receptor agonist with affinity to

PPARα and PPARγ, proposed for type 2 diabetes.
The drug had completed several phase III clinical trials, however in May, 2006
AstraZeneca announced that it had discontinued further development.

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7. Other insulin analogs

An insulin analog is an altered from of insulin, different from any occurring in
nature, but still available to the human body for performing the same action as human
insulin in terms of glycemic control. Through genetic engineering of the underlying DNA,
the amino acid sequence of insulin can be changed to alter its ADME (absorption,
distribution, metabolism, and excretion) characteristics. Officially, the U.S. Food and Drug
Administration (FDA) refers to these as "insulin receptor ligands", although they are more
commonly referred to as insulin analogs.
These modifications have been used to create two types of insulin analogs: those
that are more readily absorbed from the injection site and therefore act faster than natural
insulin injected subcutaneously, intended to supply the bolus level of insulin needed after a
meal; and those that are released slowly over a period of between 8 and 24 hours, intended
to supply the basal level of insulin for the day. Insulin analog was first manufactured by
Eli Lilly and Company.

7.1 Animal insulin

The amino acid sequence for insulin is almost the same in different mammals.
Porcine insulin has only a single amino acid variation from the human variety, and bovine
insulin varies by three amino acids. Both are active on the human receptor with
approximately the same strength. Prior to the introduction of biosynthetic human insulin,
insulin derived from sharks was widely used in Japan. Even insulin from some species of
fish may be effective in humans. Non-human insulins can cause allergic reactions in a tiny
number of people, as can genetically engineered "human" insulin. Synthetic "human"
insulin has largely replaced animal insulin. With the advent of high-pressure liquid
chromatography (HPLC) equipment, the level of purification of animal-sourced insulins
has reached as high as 99%, whereas the purity level of synthetic human insulins made via
recombinant DNA has only attained a maximum purity level of 97%, which raises
questions about the claim of synthetic insulin's purity relative to animal-sourced insulin
varieties.

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7.2 Chemically and enzymatically modified insulins

Before biosynthetic human recombinant analogues were available, porcine insulin
was chemically converted into human insulin. Chemical modifications of the amino acid
side chains at the N-terminus and/or the C-terminus were made in order to alter the ADME
characteristics of the analogue. Novo Nordisk was able to enzymatically convert porcine
insulin into 'human' insulin by removing the single amino acid that varies from the human
variety, and chemically adding the correct one.

7.3 Non hexameric insulin analogs

Unmodified human and porcine insulins tend to complex with zinc in the blood,
forming hexamers. Insulin in the form of a hexamer will not bind to its receptors, so the
hexamer has to slowly equilibrate back into its monomers to be biologically useful.
Hexameric insulin delivered subcutaneously is not readily available for the body when
insulin is needed in larger doses, such as after a meal (although this is more a function of
subcutaneously administered insulin, as intravenously dosed insulin is distributed rapidly
to the cell receptors, and therefore, avoids this problem). Zinc combinations of insulin are
used for slow release of basal insulin. Basal insulin is the amount the body needs through
the day excluding the amount needed after meals. Non hexameric insulins were developed
to be faster acting and to replace the injection of normal unmodified insulin before a meal.

7.4 Shifted isoelectric point insulins

Normal unmodified insulin is soluble at physiological pH. Analogues have been
created that have a shifted isoelectric point so that they exist in a solubility equilibrium in
which most precipitates out but slowly dissolves in the bloodstream and is eventually
excreted by the kidneys. These insulin analogues are used to replace the basal level of
insulin, and may be effective over a period of about 24 hours. However, some insulin
analogues, such as insulin detemir, bind to albumin rather than fat like earlier insulin
varieties, and results from long-term usage (e.g. more than 10 years) have never been
released.

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7.5 Carcinogenicity
All insulin analogs must be tested for carcinogenicity, as insulin engages in cross-
talk with IGF pathways, which can cause abnormal cell growth and tumorigenesis.
Modifications to insulin always carry the risk of unintentionally enhancing IGF signalling
in addition to the desired pharmacological properties.

 Insulin aspart
Chemical data
FORMULA C256H381N65O79S6
MOLECULAR MASS 5825.8 g/mol
ROUTES Subcutaneous

Insulin aspart (marketed by Novo Nordisk as "NovoLog/NovoRapid") is a fast

acting insulin analogue. It was created through recombinant DNA technology so that the
amino acid, B28, which is normally proline, is substituted with an aspartic acid residue.
This analogue has increased charge repulsion, which prevents the formation of hexamers,
to create a faster acting insulin. The sequence was inserted into the yeast genome, and the
yeast expressed the insulin analogue, which was then harvested from a bioreactor.
The components of insulin aspart are as follows: Metal ion – zinc (19.6 ug/mL)
Buffer – disodium hydrogen phosphate dihydrate (1.25 mg/mL) Preservative – m-cresol
(1.72 mg/mL) and phenol (1.50 mg/mL) Isotonicity agent – glycerin (16 mg/mL) and
sodium chloride (0.58 mg/mL). The pH of insulin aspart is 7.2-7.6.
According to JDRF, insulin aspart was approved for marketing in the United States
by the Food and Drug Administration in June 2000.

 Insulin glargine
Systemic (IUPAC) Name
Recombinant human insulin
Chemical data
FORMULA C267H408N72O77S6
MOLECULAR MASS 6063 g/mol
ROUTES Subcutaneous

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Insulin glargine, marketed by Sanofi-Aventis under the name Lantus, is a long-

acting basal insulin analogue, given once daily to help control the blood sugar level of
those with diabetes. Its advantage is that it has a duration of action of 24 hours, with a
"less peaked" profile than NPH. Thus, it more closely resembles the basal insulin secretion
of the normal pancreatic beta cells. Sometimes, in type 2 diabetes and in combination with
a short acting sulfonylurea (drugs which stimulate the pancreas to make more insulin), it
can offer moderate control of serum glucose levels. In the absence of endogenous
insulin—Type 1 diabetes, depleted type two (in some cases) or latent autoimmune diabetes
of adults in late stage—Lantus needs the support of fast acting insulin taken with food to
reduce the effect of prandially derived glucose. It is fasting glucose elevation which more
significantly affects HbA1c and thus determines the progression of the long-term
complications of diabetes mellitus.

 Insulin detemir

Structure

Chemical data
FORMULA C267H402N64O76S6
MOLECULAR MASS 5913 gm/mol
Pharmacokinetic data
BIOAVAIBILITY 60% (when administered s.c.)
HALF LIFE 5-7 hours
ROUTES Subcutaneous

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Insulin detemir is a long-acting human insulin analogue for maintaining the basal
level of insulin. Novo Nordisk markets it under the trade name Levemir. It is an insulin
analogue in which a fatty acid (myristic acid) is bound to the lysine amino acid at position
B29 . It is quickly resorbed after which it binds to albumin in the blood through the fat
acid at position B29. It then slowly dissociates from this complex.

 Insulin lispro
Chemical data
FORMULA C257H389N65O77S6
MOLECULAR MASS 5813.63 g/mol

Insulin lispro (marketed by Eli Lilly and Company as "Humalog") is a fast acting
insulin analogue; it was the first insulin analogue.

 Insulin glulisine
Chemical data
FORMULA C258H384N64O78S6
MOLECULAR MASS 5823 gm/mol
ROUTES Subcutaneous

Insulin glulisine is a rapid-acting insulin analogue that differs from human insulin
in that the amino acid asparagine at position B3 is replaced by lysine and the lysine in
position B29 is replaced by glutamic acid. Chemically, it is 3B-lysine-29B-glutamic acid-
human insulin, has the empirical formula C258H384N64O78S6 and a molecular weight of
5823. It was developed by Sanofi-Aventis and sold under the trade name Apidra. When
injected subcutaneously, it appears in the blood earlier and at higher concentrations than
human insulin. When used as a meal time insulin, the dose should be given within 15
minutes before a meal or within 20 minutes after starting a meal.

 NPH insulin
NPH insulin; also known as Humulin N, Novolin N,Novolin NPH, NPH Lletin II,
and isophane insulin, marketed by Eli Lilly and Company under the name Humulin N, is
an intermediate-acting insulin given to help control the blood sugar level of those with
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diabetes. NPH stands for Neutral Protamine Hagedorn and was created in 1936 when
Nordisk formulated "isophane" porcine insulin by adding Neutral Protamine to regular
insulin. It was dubbed Neutral Protamine Hagedorn or NPH.
This is a suspension of crystalline zinc insulin combined with the positively
charged polypeptide, protamine. When injected subcutaneously, it has an intermediate
duration of action, meaning longer than that of regular insulin, but shorter than ultralente,
glargine or detemir.

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8. Other analogs
8.1 α-Glucosidase inhibitor
α-Glucosidase inhibitors are oral anti-diabetic drugs used for diabetes mellitus type
2 that work by preventing the digestion of carbohydrates (such as starch and table sugar).
Carbohydrates are normally converted into simple sugars (monosaccharides), which can be
absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of
carbohydrates on blood sugar.

8.1.1 Examples and differences

Examples of alpha-glucosidase inhibitors include:
 Acarbose- Precose
 Miglitol - Glyset
 Voglibose
Even though the drugs have a similar mechanism of action, there are subtle
differences between acarbose and miglitol. Acarbose is an oligosaccharide, whereas
miglitol resembles a monosaccharide. Miglitol is fairly well-absorbed by the body, as
opposed to acarbose. Moreover, acarbose inhibits pancreatic alpha-amylase in addition to
alpha-glucosidase.

8.1.2 Natural α glucosidase inhibitors

Research has shown the culinary mushroom Maitake (Grifola frondosa) has a
hypoglycemic effect. The reason Maitake lowers blood sugar is due to the fact the
mushroom naturally contains a alpha glucosidase inhibitor.

8.1.3 Mechanism of action

Alpha-glucosidase inhibitors are competitive, reversible inhibitors of pancreatic α-
amylase and membrane-bound intestinal α-glucosidase hydrolase enzymes. Acarbose, the
first α-glucosidase inhibitor discovered, is a nitrogen-containing pseudotetrasaccharide,
while miglitol is a synthetic analog of 1-deoxynojirimycin. The mechanism of action of
these inhibitors is similar but not identical. They bind competitively to the oligosaccharide
binding site of the α-glucosidase enzymes, thereby preventing enzymatic hydrolysis.
Acarbose binding affinity for the α-glucosidase enzymes is: glycoamylase > sucrase >

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maltase > dextranase. Acarbose has little affinity for isomaltase and no affinity for the α-
glucosidase enzymes, such as lactase. Miglitol is a more potent inhibitor of sucrase and
maltase that acarbose, has no effect on α-amylase, but does inhibit intestinal isomaltose.
The major side effects of the α-glucosidase inhibitors are related to gastrointestinal
disturbances. These occur in approximately 25-30% of diabetic patients, and include
flatulence, diarrhea, bloating, and abdominal discomfort. Daily dose of acabose and
miglitol is 25-100mg.

8.1.4 SAR of α-Glucosidase inhibitors

An extensive search for α-Glucosidase inhibitors from microbial cultures led to the
isolation of acarbose from an actinomycete. Extensive structure activity investigations
revealed that active α-glucosidase inhibitors have a common pharmacophore, comprising a
substituted cyclohexane ring and a 4,6-dideoxy-4-amino-D-glucose unit known as
carvosine. It appears that the secondary amino group of this core structure prevents an
essensial carboxyl group of the α-glucosidase from protonating the glycosidic oxygen
bonds of the substrate. Most recently, screening programs of small molecules have yielded
several other α-glucosidase inhibitors resembling simple amino sugar as miglitol and
voglibose.

 Acarbose

Structure

Systemic (IUPAC) Name

(2R,3R,4R,5S,6R)-5-{[(2R,3R,4R,5S,6R)-5- {[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl- 5-
{[(1S,4R,5S,6S)-4,5,6-trihydroxy-3- (hydroxymethyl)cyclohex-2-en-1-yl]amino} tetrahydro-2H-pyran-2-
yl]oxy}-3,4-dihydroxy- 6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}- 6-(hydroxymethyl)tetrahydro-
2H-pyran-2,3,4-triol

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Chemical data
FORMULA C25H43NO18
MOLECULAR MASS 645.605 g/mol
Pharmacokinetic data
BIOAVAIBILITY Extremely low
METABOLISM Gastrointestinal tract
HALF LIFEca 2 hours
EXECRETION Renal (less than 2%)
ROUTES Oral

It is used in the control and management of Type 2 diabetes mellitus.

 Mechanism of Action
The drug, which is obtained from the microorganism Actinoplane utahensis, is
found to a complex oligosaccharide that specifically delays digestion of indigested
carbohydrates, thereby causing in a smaller rise in blood glucose levels soonafter meals. It
fails to increase insulin secretion; and its antihyperglycemic action is usually mediated by
a sort of competitive, reversible inhibition of pancreatic α-amylase membrane-bound
intestinal α-glucosidase hydrolase enzymes. The drug is metabolized solely within the GI
tract, chiefly by intestinal bacteria but also by diagestive enzymes.

 Miglitol

Structure

Systemic (IUPAC) Name

(2R,3R,4R,5S)-1-(2-hydroxyethyl)-2-(hydroxymethyl)piperidine-3,4,5-triol
Chemical data
FORMULA C8H17NO5
MOLECULAR MASS 207.224 g/mol
Pharmacokinetic data
BIOAVAIBILITY Dose-dependent

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PROTEIN BINDING Negligible (<4.0%)

HALF LIFE 2 hours
EXECRETION Renal (95%)
ROUTES Oral

It also lowers blood-glucose level.

 Mechanism of Action
It resembles closely to a sugar, having the heterocyclic nitrogen serving as an
isosteric replacement of the ‘sugar oxygen’. The critical alteration in its structure enables
its recognition by the α-glycosidase as a substrate. The ultimate outcome is the overall
competitive inhibition of the enzyme which eventually delays complex carbohydrate
absorption from the ensuing GI tract.

 Voglibose

Structure

Systemic (IUPAC) Name

(1S,2S,3R,4S,5S)-5-(1,3-dihydroxypropan-2-ylamino)-1-(hydroxymethyl)cyclohexane-1,2,3,4-tetraol
Chemical data
FORMULA C10H21NO7
MOLECULAR MASS 267.28 g/mol

Voglibose (trade name Voglib, marketed by Mascot Health Series) is an alpha-

glucosidase inhibitor used for lowering post-prandial blood glucose levels in people with
diabetes mellitus. Postprandial hyperglycemia (PPHG) is primarily due to first phase
insulin secretion. Alpha glucosidase inhibitors delay glucose absorption at the intestine
level and thereby prevent sudden surge of glucose after a meal. There are three drugs
which belong to this class, acarbose, miglitol and voglibose, of which voglibose is the
newest. Voglibose scores over both acarbose and miglitol in terms of side effect profile.

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8.2 Amylin
8.2.1 Islet amyloid polypeptide

Figure No. 8.1 Amino acid sequence of amylin with disulfide bridge and cleavage sites of
insulin degrading enzyme indicated with arrows

Amylin, or Islet Amyloid Polypeptide (IAPP), is a 37-residue peptide hormone

secreted by pancreatic β-cells at the same time as insulin (in a roughly 1:100
amylin:insulin ratio).
8.2.2 Pharmacology
Synthetic amylin, or pramlintide (brand name Symlin), was recently approved for
adult use in patients with both diabetes mellitus type 1 and diabetes mellitus type 2. Insulin
and pramlintide, injected separately but both before a meal, work together to control the
post-prandial glucose excursion.
Amylin is degraded in part by insulin-degrading enzyme.
8.2.3 Receptors
There appears to be at least three distinct receptor complexes that bind with high
affinity to amylin. All three complexes contain the calcitonin receptor at the core, plus one
of three receptor activity-modifying proteins, RAMP1, RAMP2, or RAMP3.

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