Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists

被引：7

作者：

Reger, Thomas S. ^{[1
]}

Zunic, Jasmine ^{[1
]}

Stock, Nicholas ^{[1
]}

Wang, Bowei ^{[1
]}

Smith, Nicholas D. ^{[1
]}

Munoz, Benito ^{[1
]}

Green, Mitchell D. ^{[2
]}

Gardner, Michael F. ^{[2
]}

James, Joyce P. ^{[2
]}

Chen, Weichao ^{[2
]}

Alves, Kenneth ^{[3
]}

Si, Qian ^{[3
]}

Treonze, Kelly M. ^{[3
]}

Lingham, Russell B. ^{[3
]}

Mumford, Richard A. ^{[3
]}

机构：

[1] Merck Res Labs, Dept Med Chem, San Diego, CA 92121 USA

[2] Merck Res Labs, Dept Drug Metab & Pharmacokinet, San Diego, CA 92121 USA

[3] Merck Res Labs, Dept Immunol & Rheumatol Res, Rahway, NJ 07065 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 03期

关键词：

SMALL-MOLECULE; MONOCLONAL-ANTIBODY; LATE ANTIGEN-4; ADHESION; DISEASE; NATALIZUMAB; INHIBITORS; DISCOVERY;

D O I：

10.1016/j.bmcl.2009.12.009

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：1173 / 1176

页数：4

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