Hydantoin based inhibitors of MMP13-Discovery of AZD6605

被引：20

作者：

De Savi, Chris ^{[1
,2
]}

Waterson, David ^{[2
]}

Pape, Andrew ^{[2
]}

Lamont, Scott ^{[2
]}

Hadley, Elma ^{[2
]}

Mills, Mark ^{[2
]}

Page, Ken M. ^{[2
]}

Bowyer, Jonathan ^{[2
]}

Maciewicz, Rose A. ^{[2
]}

机构：

[1] AstraZeneca R&D Boston, Oncol Innovat Med, Waltham, MA 02451 USA

[2] AstraZeneca R&D, Resp & Inflammat Innovat Med, SE-43813 Molndal, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 16期

关键词：

MMP13; Hydantoin; Zinc binder; Cyp P450; Lead optimisation; OSTEOARTHRITIS; CLASSIFICATION; OPTIMIZATION; BINDING; MODEL;

D O I：

10.1016/j.bmcl.2013.05.089

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：

Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：4705 / 4712

页数：8