NOVEL NONNUCLEOSIDE INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REVERSE-TRANSCRIPTASE .5. 4-SUBSTITUTED AND 2,4-DISUBSTITUTED ANALOGS OF NEVIRAPINE

被引：41

作者：

KELLY, TA

PROUDFOOT, JR

MCNEIL, DW

PATEL, UR

DAVID, E

HARGRAVE, KD

GROB, PM

CARDOZO, M

AGARWAL, A

ADAMS, J

机构：

[1] Research and Development Center, Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut 06877, 900 Ridgebury Road

[2] MyoGenics Inc, Cambridge, MA 02139

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1995年 / 38卷 / 24期

关键词：

D O I：

10.1021/jm00024a011

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-PT) 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.

引用

页码：4839 / 4847

页数：9

共 15 条

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