Discovery of γ-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor α converting enzyme:: Design, synthesis, and structure-activity relationships

被引：116

作者：

Duan, JJW ^{[1
]}

Chen, LH

Wasserman, ZR

Lu, ZH

Liu, RQ

Covington, MB

Qian, MX

Hardman, KD

Magolda, RL

Newton, RC

Christ, DD

Wexler, RR

Decicco, CP

机构：

[1] Bristol Myers Squibb Co, Discovery Chem, Expt Stn, Struct Biol & Mol Design Grp, Wilmington, DE 19880 USA

[2] Bristol Myers Squibb Co, Discovery Chem, Expt Stn, Dept Inflammatory Dis Res, Wilmington, DE 19880 USA

[3] Bristol Myers Squibb Co, Discovery Chem, Expt Stn, Dept Metab & Pharmacokinet, Wilmington, DE 19880 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2002年 / 45卷 / 23期

关键词：

D O I：

10.1021/jm0255670

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

New gamma-lactam. TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.

引用

页码：4954 / 4957

页数：4

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