Structure-based design of nonpeptidic HIV protease inhibitors from a cyclooctylpyranone lead structure.
Basic Information
ID: ALA1128181
Journal: J Med Chem
Title: Structure-based design of nonpeptidic HIV protease inhibitors from a cyclooctylpyranone lead structure.
Authors: Romines KR, Watenpaugh KD, Howe WJ, Tomich PK, Lovasz KD, Morris JK, Janakiraman MN, Lynn JC, Horng MM, Chong KT.
Abstract: 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.
CiteXplore: 7473573
DOI: 10.1021/jm00022a011
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