title: Expanded-spectrum nonnucleoside reverse transcriptase inhibitors inhibit clinically relevant mutant variants of human immunodeficiency virus type 1.
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.
authors.affiliation: DuPont Pharmaceuticals Co., Experimental Station, Wilmington, Delaware 19880-0500, USA. Jeffrey.W.Corbet@DuPontPharma.com
authors.forename: J W
authors.initials: JW
authors.lastname: Corbett
authors.forename: S S
authors.initials: SS
authors.lastname: Ko
authors.forename: J D
authors.initials: JD
authors.lastname: Rodgers
authors.forename: S
authors.initials: S
authors.lastname: Jeffrey
authors.forename: L T
authors.initials: LT
authors.lastname: Bacheler
authors.forename: R M
authors.initials: RM
authors.lastname: Klabe
authors.forename: S
authors.initials: S
authors.lastname: Diamond
authors.forename: C M
authors.initials: CM
authors.lastname: Lai
authors.forename: S R
authors.initials: SR
authors.lastname: Rabel
authors.forename: J A
authors.initials: JA
authors.lastname: Saye
authors.forename: S P
authors.initials: SP
authors.lastname: Adams
authors.forename: G L
authors.initials: GL
authors.lastname: Trainor
authors.forename: P S
authors.initials: PS
authors.lastname: Anderson
authors.forename: S K
authors.initials: SK
authors.lastname: Erickson-Viitanen
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics*; D006207:Half-Life; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D009154:Mutation / Q000502:physiology*; D002679:Pan troglodytes; D011485:Protein Binding; D018894:Reverse Transcriptase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism
chemical_list: D019380:Anti-HIV Agents; D001798:Blood Proteins; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase