       Document 0663
 DOCN  M9630663
 TI    Novel non-nucleoside inhibitors of human immunodeficiency virus type 1
       reverse transcriptase. 5. 4-Substituted and 2,4-disubstituted analogs of
       nevirapine.
 DT    9603
 AU    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.
 SO    J Med Chem. 1995 Nov 24;38(24):4839-47. Unique Identifier : AIDSLINE
       MED/96083812
 AB    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.
 DE    Comparative Study  Human  HIV-1  Models, Molecular  Molecular
       Conformation  Pyridines/*CHEMISTRY/CHEMICAL SYNTHESIS  Reverse
       Transcriptase Inhibitors/*CHEMISTRY/CHEMICAL SYNTHESIS
       Structure-Activity Relationship  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

