N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2)

被引：52

作者：

Gilbert, Adam M. ^{[1
]}

Bursavich, Matthew G. ^{[1
]}

Lombardi, Sabrina ^{[1
]}

Georgiadis, Katy E. ^{[2
]}

Reifenberg, Erica ^{[2
]}

Flannery, Carl R. ^{[2
]}

Morris, Elisabeth A. ^{[2
]}

机构：

[1] Wyeth Res, Exploratory Med Chem Chem & Screening Sci, Pearl River, NY 10965 USA

[2] Wyeth Res, Womens Hlth & Musculoskeletal Biol, Cambridge, MA 02140 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 24期

关键词：

ADAMTS-5; ADAMTS-4; Aggrecanase-2; Aggrecanase-1; Osteoarthritis; Metalloproteases;

D O I：

10.1016/j.bmcl.2008.10.065

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared. Selected compounds 10, 14, 25, and 53 show sub-mu M ADAMTS-5 potency and good selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP-13, and MMP-12. Compound 53 shows a good balance of potent ADAMTS-5 inhibition, moderate CYP3A4 inhibition and good rat liver microsome stability. This series of compounds represents progress towards selective ADAMTS-5 inhibitors as disease modifying osteoarthritis agents. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6454 / 6457

页数：4

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