Synthesis and activity of tryptophan sulfonamide derivatives as novel non-hydroxamate TNF-α converting enzyme (TACE) inhibitors

被引：26

作者：

Park, Kaapjoo ^{[1
]}

Gopalsamy, Ariamala ^{[1
]}

Aplasca, Alexis ^{[1
]}

Ellingboe, John W. ^{[1
]}

Xu, Weixin ^{[2
]}

Zhang, Yuhua ^{[3
]}

Levin, Jeremy I. ^{[1
]}

机构：

[1] Wyeth Res, Chem Sci, Pearl River, NY 10965 USA

[2] Wyeth Res, Chem Sci, Cambridge, MA 02140 USA

[3] Wyeth Res, Inflammat, Cambridge, MA 02140 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 11期

关键词：

Non-hydroxamate; TNF-alpha converting enzyme (TACE) inhibitor; Tryptophan sulfonamide derivatives; Martix metalloprotease (MMP); TUMOR-NECROSIS-FACTOR; MATRIX-METALLOPROTEINASE INHIBITORS; STRUCTURE-BASED DESIGN; RHEUMATOID-ARTHRITIS; SELECTIVE INHIBITORS; THERAPEUTIC APPLICATION; PART; IDENTIFICATION; DISCOVERY; POCKET;

D O I：

10.1016/j.bmc.2009.04.033

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1' moiety was identified as inhibitors of TNF-alpha converting enzyme (TACE). The structure-activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy) phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl) propanoic acid (12p) has the best in vitro potency against isolated TACE enzyme with an IC50 of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：3857 / 3865

页数：9

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