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      Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors Inhibit Clinically Relevant Mutant Variants of Human Immunodeficiency Virus Type 1

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          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(1 H)quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3,4-dihydro-2(1 H)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.

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          Author and article information

          Journal
          Antimicrobial Agents and Chemotherapy
          Antimicrob. Agents Chemother.
          American Society for Microbiology
          0066-4804
          1098-6596
          December 01 1999
          December 01 1999
          December 01 1999
          December 01 1999
          : 43
          : 12
          : 2893-2897
          Article
          10.1128/AAC.43.12.2893
          89583
          10582878
          b00bc71b-79ec-469d-9687-c20a5d7fbd9c
          © 1999
          Product

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