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

被引:47
作者
DeLucca, GV
Liang, J
Aldrich, PE
Calabrese, J
Cordova, B
Klabe, RM
Rayner, MM
Chang, CH
机构
[1] DuPont Merck Pharmaceutical Company, Experimental Station, Wilmington, DE 19880-0500
[2] DuPont, CR and D Experimental Station, Wilmington, DE 19880-0228
[3] DuPont Merck Pharmaceutical Co., Experimental Station, Wilmington, DE 19880-0228
关键词
D O I
10.1021/jm970081i
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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(11) 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 K-i = 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.
引用
收藏
页码:1707 / 1719
页数:13
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