A combinatorial library of indinavir analogues and its in vitro and in vivo studies.
A combinatorial library of 300HIV protease inhibitors has been synthesized. The library was screened against recombinant wild-type and mutant HIV-1 protease enzymes. The pharmacokinetics of the library was evaluated by dosing in dogs. Compounds that are notably more potent than indinavir and have favorable pharmacokinetic properties were identified.
Cheng
Yuan
Y
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. yuan_cheng@merck.com
Rano
Thomas A
TA
Huening
Tracy T
TT
Zhang
Fengqi
F
Lu
Zhijian
Z
Schleif
William A
WA
Gabryelski
Lori
L
Olsen
David B
DB
Stahlhut
Mark
M
Kuo
Lawrence C
LC
Lin
Jiunn H
JH
Xu
Xin
X
Jin
Lixia
L
Olah
Timothy V
TV
McLoughlin
Debra A
DA
King
Rick C
RC
Chapman
Kevin T
KT
Tata
James R
JR
D000818:Animals; D019540:Area Under Curve; D020650:Combinatorial Chemistry Techniques; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000254:growth & development; D006801:Humans; D019469:Indinavir / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008657:Metabolic Clearance Rate; D009154:Mutation; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D017320:HIV Protease Inhibitors; D019469:Indinavir