Hongfeng Deng; Heather O’Keefe; 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’Donovan; 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
J. Med. Chem., 2012, 55, 16, 7061-7079
https://doi.org/10.1021/jm300449x

Abstract

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-1β/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation.