Discovery of Highly Potent and Selective Small Molecule ADAMTS-5 Inhibitors That Inhibit Human Cartilage Degradation via Encoded Library Technology (ELT)

被引：105

作者：

Deng, Hongfeng ^{[1
]}

O'Keefe, Heather ^{[1
]}

Davie, Christopher P. ^{[1
]}

Lind, Kenneth E. ^{[1
]}

Acharya, Raksha A. ^{[1
]}

Franklin, G. Joseph ^{[1
]}

Larkin, Jonathan ^{[2
]}

Matico, Rosalie ^{[3
]}

Neeb, Michael ^{[4
]}

Thompson, Monique M. ^{[3
]}

Lohr, Thomas ^{[2
]}

Gross, Jeffrey W. ^{[5
]}

Centrella, Paolo A. ^{[1
]}

O'Donovan, Gary K. ^{[1
]}

Bedard, Katie L. ^{[1
]}

van Vloten, Kurt ^{[1
]}

Mataruse, Sibongile ^{[1
]}

Skinner, Steven R. ^{[1
]}

Belyanskaya, Svetlana L. ^{[1
]}

Carpenter, Tiffany Y. ^{[6
]}

Shearer, Todd W. ^{[6
]}

Clark, Matthew A. ^{[1
]}

Cuozzo, John W. ^{[1
]}

Arico-Muendel, Christopher C. ^{[1
]}

Morgan, Barry A. ^{[1
]}

机构：

[1] GlaxoSmithKline, ELT Boston, Platform Technol & Sci, Waltham, MA USA

[2] GlaxoSmithKline, Biopharm Discovery, Med Discovery & Dev, Upper Merion, PA USA

[3] GlaxoSmithKline, Platform Technol & Sci, Biol Reagent & Assay Dev, Upper Providence, PA USA

[4] GlaxoSmithlaine, Med Discovery & Dev, Ctr Excellence External Drug Discovery, Upper Merion, PA USA

[5] GlaxoSmithKline, Screening & Compound Profiling, Platform Technol & Sci, Upper Providence, PA USA

[6] GlaxoSmithKline, Med Discovery & Dev, Muscle Metab Discovery Performance Unit, Res Triangle Pk, NC USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 16期

关键词：

AGGRECAN DEGRADATION; OSTEOARTHRITIS; CLONING;

D O I：

10.1021/jm300449x

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The metalloprotease ADAMTS-5 is considered a potential target for the treatment of osteoarthritis. To identify selective inhibitors of ADAMTS-5, we employed encoded library technology (ELT), which enables affinity selection of small molecule binders from complex mixtures by DNA tagging. Selection of ADAMTS-5 against a four-billion member ELT library led to a novel inhibitor scaffold not containing a classical zinc-binding functionality. One exemplar, (R)-N-((1-(4-(but-3-en-1-ylamino)-6-(((2-(thiophen-2-yl)thiazol-4-yl)methyl)amino)-1,3,5-triazin-2-yl)pyrrolidin-2-yl)methyl)-4-propylbenzenesulfonamide (8), inhibited ADAMTS-5 with IC50 = 30 nM, showing >50-fold selectivity against ADAMTS-4 and >1000-fold selectivity against ADAMTS-1, ADAMTS-13, MMP-13, and TACE. Extensive SAR studies showed that potency and physicochemical properties of the scaffold could be further improved. Furthermore, in a human osteoarthritis cartilage explant study, compounds 8 and 15f inhibited aggrecanase-mediated (374)ARGS neoepitope release from aggrecan and glycosaminoglycan in response to IL-1 beta/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation.

引用

页码：7061 / 7079

页数：19

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