Prodrugs

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.

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

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

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

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.

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.

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

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

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).

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

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

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