Prodrugs are drugs designed to temporarily improve properties like solubility or membrane permeability by relying on metabolic processes to generate the active drug form. Common functional groups used in prodrugs include esters, which are hydrolyzed by esterases. However, esterase levels and specificities vary between species, making preclinical testing of prodrugs difficult. Examples given include the angiotensin-converting enzyme inhibitor enalapril, which is a prodrug of the active enalaprilate, and Tamiflu, which is a prodrug of oseltamavir that improves oral availability. Prodrugs can also convert polar to nonpolar groups or add extensions to make esters more readily hydro

1. Prodrugs

2. • Sometimes drugs are designed to make use of
metabolic processes in order to generate their active
form.
• This is done in order to improve some selected
property of the molecule, such as water solubility or
ability to cross a membrane, temporarily.

3. • Prodrugs currently constitute 5% of known
drugs and a larger percentage of new drugs

4. • Most common (biologically labile) functional
groups utilized in prodrug design are shown
above.

5. • Esters are the most commonly employed
prodrugs.
• Numerous catalytic esterases are present in
vivo to hydrolyze simple esters.
Prodrug Active Form of Drug

6. • However, different species have differing amounts and types of
esterases with different substrate specificities and different rates of
hydrolysis.
• This can make it difficult for pharmaceutical companies to generate
accurate preclinical models in which to evaluate their candidate
prodrug.

7. • One example is the monoethyl ester of enalaprilat, which is called enalapril.
• Enalaprilate (upper left) was first discovered as an inhibitor of angiotensin converting
enzyme (ACE) and used to treat hypertension.
• Due to its high polarity, note two COOH’s, it was not orally bioavailable, and thus
needed to be administered by injection.
• The monomethyl ester, enalapril (upper right) is orally bioavailable.

8. • Another example is the anti-viral agent
Oseltamavir (Tamiflu®) shown above
• Notice that the oral bioavailability is improved
by employing the ethyl ester of the carboxylic
acid

9. • Conversely, such a strategy can also be used to
convert an alcohol to a more lipophilic moiety,
as shown above.
Diacetate ester of the corresponding diol
(penciclovir)
Famciclovir

10. • Sometimes, in order to improve the esterase
hydrolytic lability, an ‘extension’ of the ester moiety
is employed in order to remove steric
encumbrances in the region of the ester carbonyl
group (thus enabling it to ‘fit’ the active site more
readily).

11. • Such a strategy is employed for pivampicillin,
as shown above.

12. • Such a strategy can also be used to
(temporarily) convert phosphate groups into
more lipophilic ester moieties, as shown
above.

13. Required Reading
• Rautio, J. et. al Prodrugs: design and clinical
applications. Nature Reviews Drug Discovery
2008, 7, 255-270.