Combinatorial diversification of indinavir: in vivo mixture dosing of an HIV protease inhibitor library.
An efficient combination solution-phase/solid-phase route enabling the diversification of the P1', P2', and P3 subsites of indinavir has been established. The synthetic sequence can facilitate the rapid generation of HIV protease inhibitors possessing more favorable pharmacokinetic properties as well as enhanced potencies. Multiple compound dosing in vivo may also accelerate the identification of potential drug candidates.
Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. thomas_rano@merck.com
T A
TA
Rano
Y
Y
Cheng
T T
TT
Huening
F
F
Zhang
W A
WA
Schleif
L
L
Gabryelski
D B
DB
Olsen
L C
LC
Kuo
J H
JH
Lin
X
X
Xu
T V
TV
Olah
D A
DA
McLoughlin
R
R
King
K T
KT
Chapman
J R
JR
Tata
D000818:Animals; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D004285:Dogs; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D019469:Indinavir / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D013601:T-Lymphocytes
D017320:HIV Protease Inhibitors; D019469:Indinavir; D016333:HIV Protease