DESIGN, SYNTHESIS, AND EVALUATION OF TETRAHYDROPYRIMIDINONES AS AN EXAMPLE OF A GENERAL-APPROACH TO NONPEPTIDE HIV PROTEASE INHIBITORS

Re-examination of the design of the cyclic urea class of HIV protease (HIVPR) inhibitors suggests a general approach to designing novel nonp eptide cyclic HIVPR inhibitors. This process involves the inversion of the stereochemical centers of the core transition-state isostere of t he linear HIVPR inhibitors and cyclization of the resulting core using an appropriate cyclizing reagent. As an example, this process is appl ied to the diamino alcohol class of HIVPR inhibitors(11) to give tetra hydropyrimidinones. Conformational analysis of the tetrahydropyrimidin ones and modeling of its interaction with the active site of HIVPR sug gested modifications which led to very potent inhibitors of HIVPR (24 with a K-i = 0.018 nM). The X-ray crystallographic structure of the co mplex 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.