Identification of Potent and Selective Hydantoin Inhibitors of Aggrecanase-1 and Aggrecanase-2 That Are Efficacious in Both Chemical and Surgical Models of Osteoarthritis

被引：22

作者：

Durham, Timothy B. ^{[1
]}

Klimkowski, Valentine J. ^{[1
]}

Rito, Christopher J. ^{[1
]}

Marimuthu, Jothirajah ^{[1
]}

Toth, James L. ^{[1
]}

Liu, Chin ^{[1
]}

Durbin, Jim D. ^{[1
]}

Stout, Stephanie L. ^{[1
]}

Adams, Lisa ^{[1
]}

Swearingen, Craig ^{[1
]}

Lin, Chaohua ^{[1
]}

Chambers, Mark G. ^{[1
]}

Thirunavukkarasu, Kannan ^{[1
]}

Wiley, Michael R. ^{[1
]}

机构：

[1] Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 24期

关键词：

HUMAN SYNOVIAL-FLUID; MATRIX-METALLOPROTEINASE; CARTILAGE DEGRADATION; INTERGLOBULAR DOMAIN; FRAGMENTS; DISEASE; ADAMTS5; BURDEN; HEALTH;

D O I：

10.1021/jm501522n

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

A disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are zinc metalloproteases commonly referred to as aggrecanase-1 and aggrecanase-2, respectively. These enzymes are involved in the degradation of aggrecan, a key component of cartilage. Inhibitors of these enzymes could be potential osteoarthritis (OA) therapies. A series of hydantoin inhibitors of ADAMTS-4 and ADAMTS-5 were identified from a screening campaign and optimized through structure-based drug design to give hydantoin 13. Hydantoin 13 had excellent selectivity over other zinc metalloproteases such as TACE, MMP2, MMP3, MMP13, and MMP14. The compound also produced efficacy in both a chemically induced and surgical model of OA in rats.

引用

页码：10476 / 10485

页数：10

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