4-Hydroxypyrones and Related Templates as Nonpeptidic HIV Protease Inhibitors

Abstract

Abstract: One promising therapeutic approach for the treatment of HIV infection is inhibition of the viral protease. Although a number of HIV protease inhibitors have been developed, many of the more potent compounds are peptide-derived structures. Since clinical use of such compounds is often hindered by poor pharmacokinetics and lengthy syntheses, interest in small, nonpeptidic HIV protease inhibitors has been growing. One of the most encouraging recent developments in the search for these structures is the advent of a new class of competitive inhibitors, the 4-hydroxypyrones. Screening efforts by researchers at The Upjohn Company and Parke-Davis Pharmaceutical Research independently identified the 4-hydroxycoumarins and the 4- hydroxypyrones as lead structures with weak inhibitory activity. Subsequent co-crystallization of these lead compounds with HIV protease showed that the 4-hydroxypyrone ring was functioning as the pharmacophore. These x-ray crystal structures also provided the basis for extensive structure-based drug design work, which led to the discovery of several potent inhibitors in both the 4-hydroxycoumarin and 4-hydroxypyrone classes. In addition, three new classes of derivatives were designed: the tetronic acids, the cycloalkypyranones, and the dihydropyrones. To date, .two compounds from The Upjohn Company have entered the clinic for phase I evaluation, a 4-hydroxypyrone and a cyclooctylpyranone. In preclinical evaluation, these candidates, which are both readily accessible synthetically, demonstrated not only promising antiviral activity, but also good pharmacokinetic profiles in rats and dogs.