Design, synthesis, and evaluation of tetrahydropyrimidinones as an example of a general approach to nonpeptide HIV protease inhibitors.

Important note: Information in this article was accurate in 1997. The state of the art may have changed since the publication date.

Design, synthesis, and evaluation of tetrahydropyrimidinones as an example of a general approach to nonpeptide HIV protease inhibitors.

J Med Chem. 1997 May 23;40(11):1707-9. Unique Identifier : AIDSLINE MED/97315875
De Lucca GV; Liang J; Aldrich PE; Calabrese J; Cordova B; Klabe RM; Rayner MM; Chang CH; DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0500,; USA.

Abstract: Re-examination of the design of the cyclic urea class of HIV protease (HIVPR) inhibitors suggests a general approach to designing novel nonpeptide cyclic HIVPR inhibitors. This process involves the inversion of the stereochemical centers of the core transition-state isostere of the linear HIVPR inhibitors and cyclization of the resulting core using an appropriate cyclizing reagent. As an example, this process is applied to the diamino alcohol class of HIVPR inhibitors to give tetrahydropyrimidinones. Conformational analysis of the tetrahydropyrimidinones and modeling of its interaction with the active site of HIVPR suggested modifications which led to very potent inhibitors of HIVPR (24 with a Ki = 0.018 nM). The X-ray crystallographic structure of the complex of 24 with HIVPR confirms the analysis and modeling predictions. The example reported in this study and other examples that are cited indicate that this process may be generally applicable to other linear inhibitors.

Keywords: *Drug Design *HIV Protease Inhibitors/CHEMICAL SYNTHESIS *Oximes/CHEMICAL SYNTHESIS *Pyrimidinones/CHEMICAL SYNTHESIS
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M9791309

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