       Document 0423
 DOCN  M9620423
 TI    Structure-based design of nonpeptidic HIV protease inhibitors from a
       cyclooctylpyranone lead structure.
 DT    9602
 AU    Romines KR; Watenpaugh KD; Howe WJ; Tomich PK; Lovasz KD; Morris JK;
       Janakiraman MN; Lynn JC; Horng MM; Chong KT; et al; Structural,
       Analytical, and Medicinal Chemistry Research, Upjohn; Laboratories,
       Kalamazoo, Michigan 49001, USA.
 SO    J Med Chem. 1995 Oct 27;38(22):4463-73. Unique Identifier : AIDSLINE
       MED/96071095
 AB    Recently, the novel cyclooctylpyranone HIV protease inhibitor 1 was
       identified in our labs, and an X-ray structure of this inhibitor
       complexed with HIV-2 protease was obtained. This crystal structure was
       used to develop two strategies for creating derivatives of 1 with
       enhanced enzyme inhibitory activity. The first strategy, substitution on
       the cyclooctyl ring, met with limited success, but provided some
       interesting information about the conformationally-flexible cycloocytyl
       ring on the inhibitors. The second strategy, substitution at the meta
       position of the aryl ring, was far more successful and generated
       compounds, such as the carboxamide derivatives 41 (Ki = 3.0 +/- 0.4 nM)
       and 36 (Ki = 4.0 +/- 0.8 nM), which were significantly more active than
       the corresponding unsubstituted cycloocytlpyranone 2 (Ki = 11.7 +/- 4.7
       nM). An X-ray crystal structure of 36 complexed with HIV-1 protease
       indicated the increase in binding affinity is most likely due to the
       additional interactions between the amide substituent and the S3 region
       of the protease.
 DE    Aspartic Proteinases/ANTAGONISTS & INHIB/CHEMISTRY/METABOLISM  Computer
       Graphics  Crystallography, X-Ray  Drug Design  HIV
       Protease/CHEMISTRY/METABOLISM  HIV Protease
       Inhibitors/CHEMISTRY/*CHEMICAL SYNTHESIS/  PHARMACOLOGY  Models,
       Molecular  Molecular Structure  Nuclear Magnetic Resonance
       Pyrones/CHEMISTRY/*CHEMICAL SYNTHESIS/PHARMACOLOGY  JOURNAL ARTICLE

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

