Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 8. 8-aryloxymethyl- and 8-arylthiomethyldipyridodiazepinones
Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 8. 8-aryloxymethyl- and 8-arylthiomethyldipyridodiazepinones
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DOI：
10.1021/jm9707030
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发表时间：
1998-07-30
影响因子：
7.3
通讯作者：
Hattox, SE
中科院分区：
文献类型：
--
作者：
Cywin, CL;Klunder, JM;Hattox, SE
奈韦拉平（I）是第一个获得监管批准的人类免疫缺陷病毒1型（HIV-1）非核苷逆转录酶（RT）抑制剂。作为围绕奈韦拉平三环核心系统的第二代项目的结果，2-氯-5，11-二氢-11-乙基-5-甲基-8-（2-（吡啶-4-基）乙基）-6H-联吡啶并[3，2-B：2 '，3'-e][1，4]二氮杂卓-6-酮（II）（1a）和2-氯-5，11-二氢-11-乙基-5-甲基-8-苯乙基-6H-联吡啶并[3，2-B：2 '，3'-e][1，4]二氮杂卓-6-酮（III）（1a）被鉴别为广谱HIV-1 RT抑制剂。提出了替换II或III的8-乙基接头的亚甲基中的任一个的详细检查。结果发现，8-芳氧基甲基和8-芳硫基甲基是针对RT效力的优选取代模式。针对一组临床显著的突变RT酶（K103 N、V106 A、G190 A、P236 L）以及在细胞毒性和体外代谢测定中进一步评价最有效的化合物。最有效的化合物是2-氯-8-苯硫基甲基类似物37，其对所有测试的HIV-1 RT酶显示出低于100 nM的活性。
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.