title: Inhibition of clinically relevant mutant variants of HIV-1 by quinazolinone non-nucleoside reverse transcriptase inhibitors.
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.
authors.affiliation: DuPont Pharmaceuticals Company, Experimental Station, Wilmington, Delaware 19880-0500, USA. jeffrey.w.corbett@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: L A
authors.initials: LA
authors.lastname: Gearhart
authors.forename: N A
authors.initials: NA
authors.lastname: Magnus
authors.forename: L T
authors.initials: LT
authors.lastname: Bacheler
authors.forename: S
authors.initials: S
authors.lastname: Diamond
authors.forename: S
authors.initials: S
authors.lastname: Jeffrey
authors.forename: R M
authors.initials: RM
authors.lastname: Klabe
authors.forename: B C
authors.initials: BC
authors.lastname: Cordova
authors.forename: S
authors.initials: S
authors.lastname: Garber
authors.forename: K
authors.initials: K
authors.lastname: Logue
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: D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D048588:Benzoxazines; D001798:Blood Proteins / Q000378:metabolism; D003521:Cyclopropanes; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D015394:Molecular Structure; D009154:Mutation; D010078:Oxazines / Q000097:blood / Q000494:pharmacology; D011485:Protein Binding; D011799:Quinazolines / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D001798:Blood Proteins; D003521:Cyclopropanes; D010078:Oxazines; D011799:Quinazolines; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; C098320:efavirenz