title: Synthesis and biological evaluation of aryl-phospho-indole as novel HIV-1 non-nucleoside reverse transcriptase inhibitors.
abstract: A novel series of 3-aryl-phospho-indole (API) non-nucleoside reverse transcriptase inhibitors of HIV-1 was developed. Chemical variation in the phosphorus linker led to the discovery of 3-phenyl-methyl-phosphinate-2-carboxamide 14, which possessed excellent potency against wild-type HIV-1 as well as viruses bearing K103N and Y181C single mutants in the reverse transcriptase gene. Chiral separation of the enantiomers showed that only R enantiomer retained the activity. The pharmacokinetic, solubility, and metabolic properties of 14 were assessed.
authors.affiliation: Laboratoires Idenix, Département de Chimie Médicinale, Montpellier, France. alexandre.francois-rene@idenix.com
authors.forename: François-René
authors.initials: FR
authors.lastname: Alexandre
authors.forename: Agnès
authors.initials: A
authors.lastname: Amador
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Bot
authors.forename: Catherine
authors.initials: C
authors.lastname: Caillet
authors.forename: Thierry
authors.initials: T
authors.lastname: Convard
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Jakubik
authors.forename: Chiara
authors.initials: C
authors.lastname: Musiu
authors.forename: Barbara
authors.initials: B
authors.lastname: Poddesu
authors.forename: Luana
authors.initials: L
authors.lastname: Vargiu
authors.forename: Michel
authors.initials: M
authors.lastname: Liuzzi
authors.forename: Arlène
authors.initials: A
authors.lastname: Roland
authors.forename: Maria
authors.initials: M
authors.lastname: Seifer
authors.forename: David
authors.initials: D
authors.lastname: Standring
authors.forename: Richard
authors.initials: R
authors.lastname: Storer
authors.forename: Cyril B
authors.initials: CB
authors.lastname: Dousson
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism*; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D009154:Mutation; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D007211:Indoles; D010721:Phosphinic Acids; D018894:Reverse Transcriptase Inhibitors; C562250:methyl 2-(aminocarbonyl)-5-chloro-1H-indol-3-yl-(phenyl)phosphinate; D054303:HIV Reverse Transcriptase