HIV protease inhibitors with picomolar potency against PI-Resistant HIV-1 by extension of the P 3 substituent

…, CA Rutkowski, LC Kuo, L Jin, JH Lin, EA Emini…

Index: Duffy, Joseph L.; Rano, Thomas A.; Kevin, Nancy J.; Chapman, Kevin T.; Schleif, William A.; Olsen, David B.; Stahlhut, Mark; Rutkowski, Carrie A.; Kuo, Lawrence C.; Jin, Lixia; Lin, Jiunn H.; Emini, Emilio A.; Tata, James R. Bioorganic and Medicinal Chemistry Letters, 2003 , vol. 13, # 15 p. 2569 - 2572

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Citation Number: 14

Abstract

A biaryl pyridylfuran P3 substituent on the hydroxyethylene isostere scaffold affords HIV protease inhibitors (PI's) with picomolar (IC50) potency against the protease enzymes from PI-resistant HIV-1 strains. Inclusion of a gem-dimethyl substituent afforded compound 3 with 100% oral bioavailability (dogs) and more than double the t1/2 of indinavir. Inhibition of multiple P450 isoforms is dependent on the regiochemistry of the pyridyl nitrogen in these ...