Orally active achiral N-hydroxyformamide inhibitors of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) for the treatment of osteoarthritis

被引：18

作者：

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

Pape, Andrew ^{[1
]}

Sawyer, Yvonne ^{[1
]}

Milne, David ^{[1
]}

Davies, Chris ^{[1
,2
]}

Cumming, John G. ^{[1
]}

Ting, Attilla ^{[1
,2
]}

Lamont, Scott ^{[1
,2
]}

Smith, Peter D. ^{[1
,2
]}

Tart, Jonathon ^{[1
,2
]}

Page, Ken ^{[1
]}

Moore, Peter ^{[1
]}

机构：

[1] AstraZeneca, Resp & Inflammat Res Area, Macclesfield SK10 4TG, Cheshire, England

[2] AstraZeneca, Oncol Innovat Med, Macclesfield SK10 4TG, Cheshire, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 11期

关键词：

ADAM-TS4; ADAM-TS5; Aggrecanase; Reverse hydroxamate; Osteoarthritis; ADAMTS FAMILY; OPTIMIZATION; EXPOSURE; CLONING;

D O I：

10.1016/j.bmcl.2011.04.028

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 new achiral class of N-hydroxyformamide inhibitor of both ADAM-TS4 and ADAM-TS5, 2 has been discovered through modification of the complex P1 group present in historical inhibitors 1. This structural change improved the DMPK properties and greatly simplified the synthesis whilst maintaining excellent cross-MMP selectivity profiles. Investigation of structure-activity and structure-property relationships in the P1 group resulted in both ADAM-TS4 selective and mixed ADAM-TS4/5 inhibitors. This led to the identification of a pre-clinical candidate with excellent bioavailability across three species and predicting once daily dosing kinetics. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：3301 / 3306

页数：6

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