Design, Synthesis, and Evaluation of Tetrahydropyrimidinones as an Example of a General Approach to Nonpeptide HIV Protease Inhibitors

Citations Over TimeTop 14% of 1997 papers

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.

Related Papers

• → A proteolytic activity in a human breast cancer cell line which is inhibited by the anticarcinogenic Bowman-Birk protease inhibitor(1994)20 cited
• → Synthesis and biological activity of potent heterocyclic thiol-based inhibitors of endothelin-converting enzyme-1(2002)11 cited
• → A unidirectional crosslinking strategy for HIV-1 protease dimerization inhibitors(2004)7 cited
• → MDL 74147, a novel selective and soluble inhibitor of human renin. Synthesis, structure-activity relationship, species and protease selectivities.(1992)23 cited
• → Inhibitors of HIV-1 Proteinase Containing 2-Heterosubstituted 4-Amino-3-hydroxy-5-phenylpentanoic Acid: Synthesis, Enzyme Inhibition, and Antiviral Activity(1994)51 cited