Structure-based design of COX-2 selectivity into flurbiprofen

被引：106

作者：

Bayly, CI ^{[1
]}

Black, WC ^{[1
]}

Léger, S ^{[1
]}

Ouimet, N ^{[1
]}

Ouellet, M ^{[1
]}

Percival, MD ^{[1
]}

机构：

[1] Merck Frosst Canada Inc, Pointe Claire, PQ H9R 4P8, Canada

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 1999年 / 9卷 / 03期

关键词：

D O I：

10.1016/S0960-894X(98)00717-3

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Comparative computer modeling of the X-ray crystal structures of cyclooxygenase isoforms COX-1 and COX-2 has led to the design of COX-2 selectivity into the nonselective inhibitor flurbiprofen. The COX-2 modeling was based on a postulated binding mode for flurbiprofen and took advantage of a small alcove in the COX-2 active site created by different positions of the Leu384 sidechain between COX-I and COX-2. The design hypothesis was tested by synthesis and biological assay of a series of flurbiprofen analogs, culminating in the discovery of several inhibitors having up to 78-fold selectivity for COX-2 over COX-1. (C) 1999 Elsevier Science Ltd. All rights reserved.

引用

页码：307 / 312

页数：6

共 15 条

[1] MECHANISM OF SELECTIVE-INHIBITION OF THE INDUCIBLE ISOFORM OF PROSTAGLANDIN G/H SYNTHASE [J].

COPELAND, RA ;

WILLIAMS, JM ;

GIANNARAS, J ;

NURNBERG, S ;

COVINGTON, M ;

PINTO, D ;

PICK, S ;

TRZASKOS, JM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (23) :11202-11206

[2] CATALYST TAILORING FOR PALLADIUM-MEDIATED CROSS COUPLING OF ARYLSTANNANES WITH VINYL TRIFLATES [J].

FARINA, V ;

ROTH, GP .

TETRAHEDRON LETTERS, 1991, 32 (34) :4243-4246

[3]

FUJII K, 1982, SYNTHESIS-STUTTGART, P456

[4] NS-398, A NOVEL NONSTEROIDAL ANTIINFLAMMATORY DRUG WITH POTENT ANALGESIC AND ANTIPYRETIC EFFECTS, WHICH CAUSES MINIMAL STOMACH LESIONS [J].

FUTAKI, N ;

YOSHIKAWA, K ;

HAMASAKA, Y ;

ARAI, I ;

HIGUCHI, S ;

IIZUKA, H ;

OTOMO, S .

GENERAL PHARMACOLOGY, 1993, 24 (01) :105-110

[5]

GANS KR, 1990, J PHARMACOL EXP THER, V254, P180

[6] Structural basis for selective inhibition of cyclooxygenase-2 by anti-inflammatory agents [J].

Kurumbail, RG ;

Stevens, AM ;

Gierse, JK ;

McDonald, JJ ;

Stegeman, RA ;

Pak, JY ;

Gildehaus, D ;

Miyashiro, JM ;

Penning, TD ;

Seibert, K ;

Isakson, PC ;

Stallings, WC .

NATURE, 1996, 384 (6610) :644-648

[7] Flexibility of the NSAID binding site in the structure of human cyclooxygenase-2 [J].

Luong, C ;

Miller, A ;

Barnett, J ;

Chow, J ;

Ramesha, C ;

Browner, MF .

NATURE STRUCTURAL BIOLOGY, 1996, 3 (11) :927-933

[8] The cation-pi interaction [J].

Ma, JC ;

Dougherty, DA .

CHEMICAL REVIEWS, 1997, 97 (05) :1303-1324

[9] EFFECT OF INHIBITOR TIME-DEPENDENCY ON SELECTIVITY TOWARDS CYCLOOXYGENASE ISOFORMS [J].

OUELLET, M ;

PERCIVAL, MD .

BIOCHEMICAL JOURNAL, 1995, 306 :247-251

[10]

PEARLMAN DA, 1995, AMBER 4 1

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