Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 8. 8-aryloxymethyl- and 8-arylthiomethyldipyridodiazepinones

被引:33
作者
Cywin, CL
Klunder, JM
Hoermann, M
Brickwood, JR
David, E
Grob, PM
Schwartz, R
Pauletti, D
Barringer, KJ
Shih, CK
Sorge, CL
Erickson, DA
Joseph, DP
Hattox, SE
机构
[1] Boehringer Ingelheim Pharmaceut Inc, Ctr Res & Dev, Dept Med Chem, Ridgefield, CT 06877 USA
[2] Boehringer Ingelheim Pharmaceut Inc, Ctr Res & Dev, Dept Inflammatory Dis, Ridgefield, CT 06877 USA
[3] Boehringer Ingelheim Pharmaceut Inc, Ctr Res & Dev, Dept Drug Metab & Pharmacokinet, Ridgefield, CT 06877 USA
关键词
D O I
10.1021/jm9707030
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Nevirapine (I) is the first human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase (RT) inhibitor to reach regulatory approval. As a result of a second generation program around the tricyclic core system of nevirapine, 2-chloro-5,11-dihydro-11-ethyl-5-methyl-8-(2-(pyridin-4-yl)ethyl)-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (II)(1a) and 2-chloro-5,11-dihydro-11- ethyl-5-methyl-8-phenylethyl-6H-dipyrido[3,2-b :2',3'-e][1,4]diazepin-6-one (III)(1a) were identified as broad spectrum HIV-1 RT inhibitors. A detailed examination of replacing either of the methylenes of the 8-ethyl linker of II or III is presented. It was found that 8-aryloxymethyl and 8-arylthiomethyl are the preferred pattern of substitution for potency against RT. The most potent compounds were further evaluated against a panel of clinically significant mutant RT enzymes (K103N, V106A, G190A, P236L) and in cytotoxicity and in vitro metabolism assays. The most potent compound was 2-chloro-8-phenylthiomethyl analogue 37 which displayed sub-100 nM activity against all HIV-1 RT enzymes tested.
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页码:2972 / 2984
页数:13
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