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Inhibition of Clinically Relevant Mutant Variants of HIV-1 by Quinazolinone Non-Nucleoside Reverse Transcriptase Inhibitors

2000; American Chemical Society; Volume: 43; Issue: 10 Linguagem: Inglês

10.1021/jm990580e

1520-4804

Jeffrey W. Corbett, Soo S. Ko, James D. Rodgers, Lisa A. Gearhart, Nicholas A. Magnus, Lee T. Bacheler, Sharon Diamond, Susan Jeffrey, Ronald M. Klabe, Beverly C. Cordova, Sena Garber, Kelly Logue, George L. Trainor, Paul Anderson, Susan Erickson‐Viitanen,

Quinazolinone synthesis and applications

A series of 4-alkenyl and 4-alkynyl-3,4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones were found to be potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type-1 (HIV-1). The 4-alkenyl-3,4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 082 and DPC 083 and the 4-alkynyl-3,4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 961 and DPC 963 were found to exhibit low nanomolar potency toward wild-type RF virus (IC90 = 2.0, 2.1, 2.0, and 1.3 nM, respectively) and various single and many multiple amino acid substituted HIV-1 mutant viruses. The increased potency is combined with favorable plasma serum protein binding as demonstrated by improvements in the percent free drug in human plasma when compared to efavirenz: 3.0%, 2.0%, 1.5%, 2.8%, and 0.2−0.5% for DPC 082, DPC 083, DPC 961, DPC 963, and efavirenz, respectively.