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.
Hydroxyimine derivatives of ketoprofen (1) and nabumetone (2) were synthesized and evaluated in vitro and in vivo as cytochrome P450-selective intermediate prodrug structures of ketones. 2 released nabumetone in vitro in the presence of isolated rat and human liver microsomes and in different recombinant human CYP isoforms. Bioconversion of 2 to both nabumetone and its active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA), was further confirmed in rats in vivo. Results indicate that hydroxyimine is a useful intermediate prodrug structure for ketone drugs.
Since CYP enzymes reside predominantly in the liver and secondarily in the small intestine, the results indicate that cyclic phosphate prodrugs represent a very feasible liver- or intestinal-targeted drug delivery strategy for drug molecules containing an alcohol functionality. This may potentially improve the efficacy and the safety profile of the alcoholic parent drugs.
A novel method for the synthesis of water-soluble ketoxime phosphate prodrugs avoiding the unwanted Beckmann rearrangement is developed. In the first step, a novel in situ prepared phosphorochloridic acid bis-(2-trimethylsilyl-ethyl) (TMSE) ester 1 reacts with the hydroxyimine 2. In the second step, the formed TMSE-phosphate triester 3 undergoes a tetrabutylammonium fluoride mediated microwave-assisted conversion into the corresponding ketoxime phosphate salt 4 without further Beckmann rearrangement.
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