Unsymmetric nonpeptidic HIV protease inhibitors containing anthranilamide as a P2' ligand |
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Authors: | RS Randad L Lubkowska MA Eissenstat SV Gulnik B Yu TN Bhat DJ Clanton T House SF Stinson JW Erickson |
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Affiliation: | Structural Biochemistry Program, AIDS Drug Screening and Development Laboratory, SAIC-Frederick, MD, USA. |
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Abstract: | A series of novel unsymmetrical anthranilamide-containing HIV protease inhibitors was designed. The structure-activity studies revealed a series of potent P2-P3' inhibitors that incorporate an anthranilamide group at the P2' position. A reduction in molecular weight and lipophilicity is achieved by a judicious choice of P2 ligands (i.e., aromatic, heteroaromatic, carbamate, and peptidic). A systematic investigation led to the 5-thiazolyl carbamate analog 8 m, which exhibited a favorable Cmax/EC50 ratio (> 30), plasma half-life (> 8 h), and potent in vitro antiviral activity (EC50 = 0.2 microM). |
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