Synthesis and activity of novel HIV protease inhibitors with improved potency against multiple PI-resistant viral strains.
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.
Duffy
Joseph L
JL
Department of Basic Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. joseph_duffy@merck.com
Kevin
Nancy J
NJ
Kirk
Brian A
BA
Chapman
Kevin T
KT
Schleif
William A
WA
Olsen
David B
DB
Stahlhut
Mark
M
Rutkowski
Carrie A
CA
Kuo
Lawrence C
LC
Jin
Lixia
L
Lin
Jiunn H
JH
Emini
Emilio A
EA
Tata
James R
JR
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
D017320:HIV Protease Inhibitors; D019469:Indinavir; D016333:HIV Protease