Discovery of highly potent and selective small molecule ADAMTS-5 inhibitors that inhibit human cartilage degradation via encoded library technology (ELT)

  • J Med Chem. 2012 Aug 23;55(16):7061-79. doi: 10.1021/jm300449x.
Hongfeng Deng  1 ,  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
Affiliations
  • 1. ELT Boston, Platform Technology and Science, GlaxoSmithKline, Waltham, Massachusetts, United States. [email protected]
PMID: 22891645 DOI: 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 IC(50) = 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-1β/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation.

Products