Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. 4. 2-Substituted dipyridodiazepinones as potent inhibitors of both wild-type and cysteine-181 HIV-1 reverse transcriptase enzymes.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

J Med Chem. 1995 Nov 24;38(24):4830-8. Unique Identifier : AIDSLINE MED/96083811
Proudfoot JR; Hargrave KD; Kapadia SR; Patel UR; Grozinger KG; McNeil DW; Cullen E; Cardozo M; Tong L; Kelly TA; et al; Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield,; Connecticut 06877, USA.

Abstract: The major cause of viral resistance to the potent human immunodeficiency virus type 1 reverse transcriptase (RT) inhibitor nevirapine is the mutation substituting cysteine for tyrosine-181 in RT (Y181C RT). An evaluation, against Y181C RT, of previously described analogs of nevirapine revealed that the 2-chlorodipyridodiazepinone 16 is an effective inhibitor of this mutant enzyme. The detailed examination of the structure-activity relationship of 2-substituted dipyridodiazepinones presented below shows that combined activity against the wild-type and Y181C enzymes is achieved with aryl substituents at the 2-position of the tricyclic ring system. In addition, the substitution pattern at C-4, N-5, and N-11 of the dipyridodiazepinone ring system optimum for inhibition of both wild-type and Y181C RT is no longer the 4-methyl-11-cyclopropyl substitution preferred against the wild-type enzyme but rather the 5-methyl-11-ethyl (or 11-cyclopropyl) pattern. The more potent 2-substituted dipyridodiazepinones were evaluated against mutant RT enzymes (L100I RT, K103N RT, P236L RT, and E138K RT) that confer resistance to other non-nucleoside RT inhibitors, and compounds 42, 62, and 67, with pyrrolyl, aminophenyl, and aminopyridyl substituents, respectively, at the 2-position, were found to be effective inhibitors of these mutant enzymes also.

Keywords: Cell Line Human HIV-1 Molecular Structure Pyridines/*CHEMISTRY/PHARMACOLOGY Reverse Transcriptase Inhibitors/*CHEMISTRY/PHARMACOLOGY Structure-Activity Relationship JOURNAL ARTICLE
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