Continued exploration of biphenylsulfonamide scaffold as a platform for aggrecanase-1 inhibition

被引：4

作者：

Hu, Yonghan ^{[1
]}

Xing, Li ^{[1
]}

Thomason, Jennifer R. ^{[1
]}

Xiang, Jason ^{[1
]}

Ipek, Manus ^{[1
]}

Guler, Satenig ^{[2
]}

Li, Huanqiu ^{[3
]}

Sabatini, Joshua ^{[1
]}

Chockalingam, Priya ^{[4
]}

Reifenberg, Erica ^{[5
]}

Sheldon, Richard ^{[4
]}

Morris, Elisabeth A. ^{[4
]}

Georgiadis, Katy E. ^{[4
]}

Tam, Steve ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Worldwide Med Chem, Cambridge, MA 02140 USA

[2] Astra Zeneca Res Ctr, Waltham, MA 02451 USA

[3] Abbott Labs, Abbott Pk, IL 60064 USA

[4] Pfizer Global Res & Dev, Inflammat & Immunol, Cambridge, MA 02140 USA

[5] Echelon Biosci, Salt Lake City, UT 84108 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 22期

关键词：

Aggrecanase-1; MMP-13; Osteoarthritis; Biphenylsulfonamide; MATRIX-METALLOPROTEINASE INHIBITORS; SELECTIVE MMP-13 INHIBITORS; BIOLOGICAL EVALUATION; POTENT; DESIGN; IDENTIFICATION; DISCOVERY; SERIES;

D O I：

10.1016/j.bmcl.2011.09.036

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Design, synthesis and structure-activity relationship of a series of biphenylsulfonamido-3-methylbutanoic acid based aggrecanase-1 inhibitors are described. In addition to robust aggrecanase-1 inhibition, these compounds also exhibit potent MMP-13 activity. In cell-based cartilage explants assay compound 48 produced 87% inhibition of proteoglycan degradation at 10 mu g/mL. Good pharmacokinetic properties were demonstrated by 46 with a half-life of 6 h and bioavailability of 23%. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：6800 / 6803

页数：4

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