PRODRUG
Prodrugs of Functional Groups
Prodrugs grouped into different types according to functional groups
and their chemical bonds;
1) Carboxylic acids and Alcohols, to form ester linkage.
2) Amines, to form mannich bases.
3) Amines, to form azo linkage.
4) Amines, to form amide linkage (rare approach).
Carboxylic acids and alcohols Prodrugs of agents that contain
carboxylic acid or alcohol functionalities can often be prepared by
conversion to an ester. This is the most common type of prodrug,
because of the ease with which the ester can be hydrolyzed to give the
active drug. Hydrolysis is usually accomplished by esterase enzymes
present in plasma and other tissues that can capable of hydrolyzing a
wide variety of ester linkages.
There are different types of esterase enzymes as
ester hydrolase
lipase
cholesterol esterase,
acetylcholine esterase,
carboxypeptidase,
Cholinesterase.
In addition to these agents, microflora present within the gut produce a
wide variety of enzymes that can hydrolyze esters. Chemical
hydrolysis of the ester linkage may also occur to some extent
An additional factor that has contributed to the popularity of the ester
prodrugs is the ease with which they can be formed. If the drug
molecule contain either carboxylic acid or alcohol functionalities, an
ester prodrug can synthesized easily.
The carboxylic acid or alcohol promoiety can be chosen to provide a
wide range of lipophilic or hydrophilic properties to the drug,
depending on what is desired. Manipulation of the steric and
electronic properties of the promoiety allows control the rate and
extent of hydrolysis. This can be an important consideration when the
active drug must be revealed at the correct point in its movement
through the biological system. When it is desired to decrease water
solubility, a nonpolar alcoholic or carboxylic acid is chosen as the
prodrug moiety. Decreasing the hydrophilicity of the compound may
yield a number of benefits, including increase absorption, decrease
dissolution in the aqueous environment of the stomach, and a longer
duration of action.
Examples of Ester Prodrugs:
Dipivefrin HCl;
it is a prodrug form of epinephrine in which the catechol hydroxyl
groups has been used in the formation of an ester linkage with pivalic
acid. It is an example of increase absorption by addition of non-polar
carboxylic acid (pivalic acid). It is used for treatment of open angle
glaucoma. The increase lipophilicity relative to epinephrine allows the
agent, when applied, to move across the membrane of the eye easily.
Hydrolysis of the ester function then occurs in the cornea,
conjunctiva, and aqueous humor to generate the active form,
epinephrine.
Using pivalic acid as promoiety, increase the steric bulk around the
scissile ester bond, which slows the ester hydrolysis relative to less
bulky groups, yet still allows this reaction to proceed after the drug
has crossed the membrane barriers of the eye. In addition to this
benefit, the catechol system is somewhat susceptible to oxidation,
and protecting the catechol as diester will prevent this oxidation and
the resulting drug inactivation.
Chloramphenicol Palmitate
chloramphenicol has unpleasant taste when given through oral rout,
this result due to the drug dissolve in the mouth and is capable for
interacting with the taste receptors. This represent a significant
problem, especially in pediatric patients, and may lead to law
compliance. A prodrug with reduce water solubility doses not dissolve
to any appreciable extent in the mouth, and therefore, does not interact
with the taste receptors. This approach has been used in the case of
antibacterial chloramphenicol, which produce a bitter taste when given
as a parent drug.
The hydrophobic palmitate ester does not dissolve to any appreciable
extent in the mouth, so there is a little chance for interaction with the
taste receptors. The ester moiety is subsequently hydrolyzed in the
GIT, and the agent is absorbed as chloramphenicol. There are other
agents that converted to ester prodrugs to overcome an unpleasant
taste, such as N-Acetyl sulfisoxazole, N-Acetyl
sulfamethoxypyridazine, Erythromycin estolate, and Clindamycin
palmitate.
Double Ester Approach
Not all carboxylic acid esters are easily hydrolyzes in vivo. Steric
inhibition around the ester in some cases prevents the prodrug from
being hydrolyzed. This is seen in the βlactams, in which it is often
desirable to increase the hydrophobicity of the agent to improve the
absorption or prevent dissolution in the stomach where acid-catalyze
decomposition may occur. Simple esters of the carboxylic acid moiety
(Ethyl, propyl, butyl, or phenyl), however, are not hydrolyzed in vivo
to the active carboxylate.
A solution to this problem was to use the so-called double-ester
approach, in which an additional ester or carbonate function is
incorporated into R2 substituent further removed from the heterocyclic
nucleus. Hydrolysis of such a function occurred readily, and the moiety
was selected so that chemical hydrolysis of second ester occurred
quickly. This is seen in the cephalosporin cefpodoxime proxetile, where
a carbonate function was used. The carbonate also susceptible to the
action of esterase enzymes, and the unstable product undergoes further
reaction to give the active carboxylate. This approach is frequently used
to improve absorption, or prevent dissolution in the stomach and the
subsequent acid-catalyzed decomposition of aminopenicilins and
second- and third-generation cephalosporins (cefuroxime and
cefpodoxime), so that these agents are administered orally.
THANK YOU
