STRUCTURE-BASED DESIGN OF NONPEPTIDIC HIV PROTEASE INHIBITORS FROM A CYCLOOCTYLPYRANONE LEAD STRUCTURE

Recently, the novel cyclooctylpyranone HIV protease inhibitor 1 was id entified in our labs, and an X-ray structure of this inhibitor complex ed with HIV-2 protease was obtained. This crystal structure was used t o develop two strategies for creating derivatives of 1 with enhanced e nzyme inhibitory activity. The first strategy, substitution on the cyc looctyl ring, met with limited success, but provided some interesting information about the conformationally-flexible cyclooctyl 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 (K-i = 3.0 +/- 0.4 nM) and 36 (K-i = 4.0 +/- 0.8 nM), which were significantly more active than the corres ponding unsubstituted cyclooctylpyranone 2 (K-i = 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 p rotease.