Highly potent HIV-1 protease inhibitors with novel tricyclic P2 ligands: design, synthesis, and protein-ligand X-ray studies.

J Med Chem 2013 Sep 15;56(17):6792-802. Epub 2013 Aug 15.

Department of Chemistry and Department of Medicinal Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.

The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor's potent antiviral activity and excellent resistance profiles.

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http://dx.doi.org/10.1021/jm400768fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800042PMC
September 2013
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