1. Academic Validation
  2. Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1

Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1

  • Antimicrob Agents Chemother. 1999 Dec;43(12):2893-7. doi: 10.1128/AAC.43.12.2893.
J W Corbett 1 S S Ko J D Rodgers S Jeffrey L T Bacheler R M Klabe S Diamond C M Lai S R Rabel J A Saye S P Adams G L Trainor P S Anderson S K Erickson-Viitanen
Affiliations

Affiliation

  • 1 DuPont Pharmaceuticals Co., Experimental Station, Wilmington, Delaware 19880-0500, USA. Jeffrey.W.Corbet@DuPontPharma.com
Abstract

A research program targeted toward the identification of expanded-spectrum nonnucleoside Reverse Transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug.

Figures
Products