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

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• 作者：Hongfeng Deng ; Heather O鈥橩eefe ; Christopher P. Davie ; Kenneth E. Lind ; Raksha A. Acharya ; G. Joseph Franklin ; Jonathan Larkin ; Rosalie Matico ; Michael Neeb ; Monique M. Thompson ; Thomas Lohr ; Jeffrey W. Gross ; Paolo A. Centrella ; Gary K. O鈥橠onovan ; Katie L. (Sargent) Bedard ; Kurt van Vloten ; Sibongile Mataruse ; Steven R. Skinner ; Svetlana L. Belyanskaya ; Tiffany Y. Carpenter ; Todd W. Shearer ; Matthew A. Clark ; John W. Cuozzo ; Christopher C. Arico-Muendel ; Barry A. Morgan
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 23, 2012
• 年：2012
• 卷：55
• 期：16
• 页码：7061-7079
• 全文大小：689K
• 年卷期：v.55,no.16(August 23, 2012)
• ISSN：1520-4804

文摘

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 ³⁷⁴ARGS neoepitope release from aggrecan and glycosaminoglycan in response to IL-1尾/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation.