2. Academic Validation
  3. Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors

Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors

  • J Med Chem. 2000 May 18;43(10):2019-30. doi: 10.1021/jm990580e.
J W Corbett 1,  S S Ko,  J D Rodgers,  L A Gearhart,  N A Magnus,  L T Bacheler,  S Diamond,  S Jeffrey,  R M Klabe,  B C Cordova,  S Garber,  K Logue,  G L Trainor,  P S Anderson,  S K Erickson-Viitanen
Affiliations

Affiliation

  • 1 DuPont Pharmaceuticals Company, Experimental Station, Wilmington, Delaware 19880-0500, USA. jeffrey.w.corbett@dupontpharma.com
PMID: 10821714 DOI: 10.1021/jm990580e
Abstract

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 (IC(90) = 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.

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