       Document 0664
 DOCN  M9630664
 TI    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.
 DT    9603
 AU    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.
 SO    J Med Chem. 1995 Nov 24;38(24):4830-8. Unique Identifier : AIDSLINE
       MED/96083811
 AB    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.
 DE    Cell Line  Human  HIV-1  Molecular Structure
       Pyridines/*CHEMISTRY/PHARMACOLOGY  Reverse Transcriptase
       Inhibitors/*CHEMISTRY/PHARMACOLOGY  Structure-Activity Relationship
       JOURNAL ARTICLE

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

