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| - Design, Synthesis, and Evaluation of Tetrahydropyrimidinones as an Exampleof a General Approach to Nonpeptide HIV Protease Inhibitors
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| - Re-examination of the design of the cyclic urea class of HIVprotease (HIVPR) inhibitors suggestsa general approach to designing novel nonpeptide cyclic HIVPRinhibitors. This process involvesthe inversion of the stereochemical centers of the coretransition-state isostere of the linearHIVPR inhibitors and cyclization of the resulting core using anappropriate cyclizing reagent.As an example, this process is applied to the diamino alcoholclass of HIVPR inhibitors11 togive tetrahydropyrimidinones. Conformational analysis of thetetrahydropyrimidinones andmodeling of its interaction with the active site of HIVPR suggestedmodifications which led tovery potent inhibitors of HIVPR (24 with aKi = 0.018 nM). The X-raycrystallographic structureof the complex of 24 with HIVPR confirms the analysis andmodeling predictions. The examplereported in this study and other examples that are cited indicate thatthis process may begenerally applicable to other linear inhibitors.
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