Prodrugs are bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect. In both drug discovery and development, prodrugs have become an established tool for improving physicochemical, biopharmaceutical or pharmacokinetic properties of pharmacologically active agents. About 5-7% of drugs approved worldwide can be classified as prodrugs, and the implementation of a prodrug approach in the early stages of drug discovery is a growing trend. To illustrate the applicability of the prodrug strategy, this article describes the most common functional groups that are amenable to prodrug design, and highlights examples of prodrugs that are either launched or are undergoing human trials.

Potentially orally bioavailable prodrugs of the antiretroviral agent 9-[2-(phosphonomethoxy)propyl]adenine (PMPA) were evaluated. Alkyl methyl carbamates were synthesized by alkylation of PMPA with the corresponding alkyl chloromethyl carbonate and N-alkyl chloromethyl carbamate reagents. The prodrugs were evaluated for in vitro antiviral activity in addition to chemical and enzymic stability. The inhibition of human immunodeficiency virus type 1 (HIV-1) strain IIIB replication in MT-2 cells by the carbonate prodrugs was found to be 2.S-S00-fold increased compared to PMPA. The alkyl methyl carbonates, except t-butyl methyl carbonate, had reasonable chemical stability at pH 2.2 and 7.4, but were rapidly converted to the corresponding monoester of PMPA in the presence of dog plasma. The alkyl methyl carbamate prodrugs such as N-t-butyl methyl carbamate were found to have high stability in vitro. Based on its chemical stability and good oral bioavailability, bis(POqPMPA (isopropyl methyl carbonate) was chosen as a clinical candidate.

There was a correlation between oral bioavailability and intestinal stability of bis-(alkoxycarbonyloxymethyl) ester prodrugs (r2 = 0.96). Lipophilicity (log P) was not a good predictor of oral bioavailability. The most labile prodrugs in dog intestinal homogenates, bis-(n-butyloxycarbonyloxymethyl) PMPA 5 and bis-(neo-pentyloxy-carbonyloxymethyl) PMPA 8 (t1/2 < 5 min) had the lowest oral bioavailabilities. Based on good oral bioavailability (30.1%), chemical and intestinal stability bis-(isopropyloxycarbonyloxymethyl) PMPA (bis-POC PMPA) 4 was selected as a candidate for clinical evaluation.

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The carboxylate function on the salicylate prodrugs of cyclic HPMPC provides an additional handle to chemically modify the lipophilicity, solubility and the biological reactivity of the prodrug. In tissue and enzymatic studies, the major degradation product is cyclic HPMPC. The salicylate ester prodrugs are attractive drug candidates for further in vivo evaluation.