Synthesis and activity of novel HIV protease inhibitors with improved potency against multiple PI-resistant viral strains

被引：12

作者：

Duffy, JL ^{[1
]}

Kevin, NJ

Kirk, BA

Chapman, KT

Schleif, WA

Olsen, DB

Stahlhut, M

Rutkowski, CA

Kuo, LC

Jin, LX

Lin, JH

Emini, EA

Tata, JR

机构：

[1] Merck Res Labs, Dept Basic Chem, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept Virus & Cell Biol, W Point, PA 19486 USA

[3] Merck Res Labs, Dept Biol Chem, W Point, PA 19486 USA

[4] Merck Res Labs, Dept Biol Struct, W Point, PA 19486 USA

[5] Merck Res Labs, Dept Drug Metab, W Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2002年 / 12卷 / 17期

关键词：

D O I：

10.1016/S0960-894X(02)00425-0

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2002 Elsevier Science Ltd. All rights reserved.

引用

收藏

页码：2423 / 2426

页数：4

相关论文

共 16 条

[1] Resistance to human immunodeficiency virus type 1 protease inhibitors [J].

Boden, D ;

Markowitz, M .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1998, 42 (11) :2775-2783

[2] INDOLES BENZOFURANS PHTHALIDES AND TOLANES VIA COPPER(1) ACETYLIDES [J].

CASTRO, CE ;

GAUGHAN, EJ ;

OWSLEY, DC .

JOURNAL OF ORGANIC CHEMISTRY, 1966, 31 (12) :4071-+

[3] Indinavir analogues with blocked metabolism sites as HIV protease inhibitors with improved pharmacological profiles and high potency against PI-resistant viral strains [J].

Cheng, Y ;

Zhang, FQ ;

Rano, TA ;

Lu, ZJ ;

Schleif, WA ;

Gabryelski, L ;

Olsen, DB ;

Stahlhut, M ;

Rutkowski, CA ;

Lin, JH ;

Jin, LX ;

Emini, EA ;

Chapman, KT ;

Tata, JR .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2002, 12 (17) :2419-2422

[4]

Chiba M, 1996, DRUG METAB DISPOS, V24, P307

[5] Hepatic and intestinal metabolism of indinavir, an HIV protease inhibitor, in rat and human microsomes - Major role of CYP3A [J].

Chiba, M ;

Hensleigh, M ;

Lin, JH .

BIOCHEMICAL PHARMACOLOGY, 1997, 53 (08) :1187-1195

[6] Genetic correlates of in vivo viral resistance to indinavir, a human immunodeficiency virus type 1 protease inhibitor [J].

Condra, JH ;

Holder, DJ ;

Schleif, WA ;

Blahy, OM ;

Danovich, RM ;

Gabryelski, LJ ;

Graham, DJ ;

Laird, D ;

Quintero, JC ;

Rhodes, A ;

Robbins, HL ;

Roth, E ;

Shivaprakash, M ;

Yang, T ;

Chodakewitz, JA ;

Deutsch, PJ ;

Leavitt, RY ;

Massari, FE ;

Mellors, JW ;

Squires, KE ;

Steigbigel, RT ;

Teppler, H ;

Emini, EA .

JOURNAL OF VIROLOGY, 1996, 70 (12) :8270-8276

[7] L-735,524 - THE DESIGN OF A POTENT AND ORALLY BIOAVAILABLE HIV PROTEASE INHIBITOR [J].

DORSEY, BD ;

LEVIN, RB ;

MCDANIEL, SL ;

VACCA, JP ;

GUARE, JP ;

DARKE, PL ;

ZUGAY, JA ;

EMINI, EA ;

SCHLEIF, WA ;

QUINTERO, JC ;

LIN, JH ;

CHEN, IW ;

HOLLOWAY, MK ;

FITZGERALD, PMD ;

AXEL, MG ;

OSTOVIC, D ;

ANDERSON, PS ;

HUFF, JR .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (21) :3443-3451

[8] THE ALKYLATION OF AMINES WITH T-ACETYLENIC CHLORIDES - PREPARATION OF STERICALLY HINDERED AMINES [J].

HENNION, GF ;

HANZEL, RS .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1960, 82 (18) :4908-4912

[9]

Kempf DJ, 2001, ANTIRETROVIRAL THERAPY, P147

[10]

Lin JH, 1996, DRUG METAB DISPOS, V24, P1111