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
收藏
页码：3857 / 3865
页数：9
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