1394122-70-3Relevant articles and documents
Discovery of highly potent and selective small molecule ADAMTS-5 inhibitors that inhibit human cartilage degradation via encoded library technology (ELT)
Deng, Hongfeng,O'Keefe, Heather,Davie, Christopher P.,Lind, Kenneth E.,Acharya, Raksha A.,Franklin, G. Joseph,Larkin, Jonathan,Matico, Rosalie,Neeb, Michael,Thompson, Monique M.,Lohr, Thomas,Gross, Jeffrey W.,Centrella, Paolo A.,O'Donovan, Gary K.,Bedard, Katie L.,Van Vloten, Kurt,Mataruse, Sibongile,Skinner, Steven R.,Belyanskaya, Svetlana L.,Carpenter, Tiffany Y.,Shearer, Todd W.,Clark, Matthew A.,Cuozzo, John W.,Arico-Muendel, Christopher C.,Morgan, Barry A.
, p. 7061 - 7079 (2012/11/07)
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-propylbenzenesulfona-mide (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.
