title: Synthesis and activity of novel HIV protease inhibitors with improved potency against multiple PI-resistant viral strains.
abstract: Substitution of the t-butylcarboxamide substituent in analogues of the HIV protease inhibitor (PI) Indinavir with a trifluoroethylamide moiety confers greater potency against both the wild-type (NL4-3) virus and PI-resistant HIV. The trifluoroethyl substituent also affords a slower clearance rate in vivo (dogs); however, this may be due to more potent inhibition of at least two P450 isoforms.
authors.affiliation: Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. joseph_duffy@merck.com
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Duffy
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Kevin
authors.forename: Brian A
authors.initials: BA
authors.lastname: Kirk
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Chapman
authors.forename: William A
authors.initials: WA
authors.lastname: Schleif
authors.forename: David B
authors.initials: DB
authors.lastname: Olsen
authors.forename: Mark
authors.initials: M
authors.lastname: Stahlhut
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Rutkowski
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Kuo
authors.forename: Lixia
authors.initials: L
authors.lastname: Jin
authors.forename: Jiunn H
authors.initials: JH
authors.lastname: Lin
authors.forename: Emilio A
authors.initials: EA
authors.lastname: Emini
authors.forename: James R
authors.initials: JR
authors.lastname: Tata
mesh_terms: D000818:Animals; D004285:Dogs; D018432:Drug Resistance, Multiple; D006678:HIV / Q000187:drug effects*; D016333:HIV Protease / Q000187:drug effects; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D020128:Inhibitory Concentration 50; D008657:Metabolic Clearance Rate; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D017320:HIV Protease Inhibitors; D019469:Indinavir; D016333:HIV Protease