Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. 5. 4-Substituted and 2,4-disubstituted analogs of nevirapine.

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

Novel non-nucleoside inhibitors of human immunodeficiency virus type 1 reverse transcriptase. 5. 4-Substituted and 2,4-disubstituted analogs of nevirapine.

J Med Chem. 1995 Nov 24;38(24):4839-47. Unique Identifier : AIDSLINE MED/96083812
Kelly TA; Proudfoot JR; McNeil DW; Patel UR; David E; Hargrave KD; Grob PM; Cardozo M; Agarwal A; Adams J; Research and Development Center, Boehringer Ingelheim; Pharmaceuticals Inc., Ridgefield, Connecticut 06877, USA.

Abstract: Molecular modeling analysis of the recently published X-ray crystal structure of nevirapine bound to wild type human immunodeficiency virus type 1 reverse transcriptase (WT-RT) indicated the presence of a lipophilic cavity proximal to the 4-position of the inhibitor. A series of 4-substituted derivatives of nevirapine were thus synthesized to assess structure-activity relationships (SARs) and to see if increased binding to this region might translate into greater activity against mutant RTs. The results show that compounds with an appropriately spaced aryl ring appended to the 4-position of the dipyridodiazepinone ring system show good activity against WT-RT. Furthermore certain derivatives appear to inhibit the Y181C mutant RT. Attempts to combine these results with the recent discovery that 2-substituents enhance activity against the Y181C mutant led to a few compounds with moderate activity against both enzymes. The SAR of these two positions, however, could not be combined in a simple fashion.

Keywords: Comparative Study Human HIV-1 Models, Molecular Molecular Conformation Pyridines/*CHEMISTRY/CHEMICAL SYNTHESIS Reverse Transcriptase Inhibitors/*CHEMISTRY/CHEMICAL SYNTHESIS Structure-Activity Relationship JOURNAL ARTICLE
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