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

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

Affiliation

  • 1 ELT Boston, Platform Technology and Science, GlaxoSmithKline, Waltham, Massachusetts, United States. hongfeng.x.deng@gsk.com
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.

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