Aza-peptide analogs as potent human immunodeficiency virus type-1 protease inhibitors with oral bioavailability

被引:63
作者
Fassler, A [1 ]
Bold, G [1 ]
Capraro, HG [1 ]
Cozens, R [1 ]
Mestan, J [1 ]
Poncioni, B [1 ]
Rosel, J [1 ]
TintelnotBlomley, M [1 ]
Lang, M [1 ]
机构
[1] CIBA GEIGY AG,DIV PHARMACEUT,RES LABS CANC & INFECT DIS,CH-4002 BASEL,SWITZERLAND
关键词
D O I
10.1021/jm960022p
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of aza-peptide analogs with a (hydroxyethyl)hydrazine isostere has been synthesized as HIV-1 protease inhibitors using a simple synthetic scheme. Structure-activity studies based on the X-ray of a previously described inhibitor-enzyme complex led to potent inhibitors with antiviral activity in the low-nanomolar range. The S-configuration of the transition-state hydroxyl group was preferred in this series. Small modifications of the P2P3 and P-2'P-3' substituents had little effect on enzyme inhibition but greatly influenced the pharmacokinetic profile. As a result of these studies, the symmetrically acylated compound 8a and its close analog 24a bearing a methyl carbamate in P-3 and an ethyl carbamate in P-3' position were identified as potent inhibitors with plasma concentrations exceeding antiviral ED(50) values 150-fold following oral application in mice.
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收藏
页码:3203 / 3216
页数:14
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