Novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 7. 8-Arylethyldipyridodiazepinones as potent broad-spectrum inhibitors of wild-type and mutant enzymes.
作者信息
Klunder J M, Hoermann M, Cywin C L, David E, Brickwood J R, Schwartz R, Barringer K J, Pauletti D, Shih C K, Erickson D A, Sorge C L, Joseph D P, Hattox S E, Adams J, Grob P M
机构信息
Departments of Medicinal Chemistry, Inflammatory Diseases, and Drug Metabolism and Pharmacokinetics, Research and Development Center, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877, USA.
出版信息
J Med Chem. 1998 Jul 30;41(16):2960-71. doi: 10.1021/jm9707028.
Like other nonnucleoside inhibitors of HIV-1 reverse transcriptase, the dipyridodiazepinone nevirapine (Viramune, 1) selects for drug resistant variants of HIV-1, both in cell culture and in patients. In particular, the mutation of residue 181 from tyrosine to cysteine (Y181C) is associated with resistance to most reported nonnucleoside inhibitors. Introduction of an arylethyl substituent at the 8-position of the tricyclic dipyridodiazepinone skeleton confers enhanced potency against Y181C RT. Several analogues of this series display good broad spectrum potency against a panel of mutant enzymes.
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