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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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    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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    † ELT Boston, Platform Technology and Science, GlaxoSmithKline, Waltham, Massachusetts, United States
    ‡ Biopharm Discovery, Medicines Discovery and Development, GlaxoSmithKline, Upper Merion, Pennsylvania, United States
    § Biological Reagent and Assay Development, Platform Technology and Science, GlaxoSmithKline, Upper Providence, Pennsylvania, United States
    ∥ Center of Excellence for External Drug Discovery, Medicines Discovery and Development, GlaxoSmithKline, Upper Merion, Pennsylvania, United States
    ⊥ Screening and Compound Profiling, Platform Technology and Science, GlaxoSmithKline, Upper Providence, Pennsylvania, United States
    # Muscle Metabolism Discovery Performance Unit, Medicines Discovery and Development, GlaxoSmithKline, Research Triangle Park, North Carolina, United States
    *For H.D.: phone, 1-781-795-4302; fax, 1-781-795-4496; e-mail, [email protected]. For C.C.A.-M.: phone, 1-781-795-4272; fax, 1-781-795-4496; e-mail, [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2012, 55, 16, 7061–7079
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    https://doi.org/10.1021/jm300449x
    Published August 14, 2012
    Copyright © 2012 American Chemical Society
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    Abstract

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    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.

    Copyright © 2012 American Chemical Society

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    The human biological samples were sourced ethically, and their research use was in accord with the terms of the informed consents. All studies were conducted after review by the GSK Institutional Animal Care and Use Committee and in accordance with the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals.

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    Experimental details for the synthesis of the DNA encoded library, the ADAMTS-5 inhibition experiment with various concentrations of ZnCl2, the substrate–inhibitor competition experiment, the solubility and artificial membrane permeability assays, and rat liver microsomal stability assay. This material is available free of charge via the Internet at http://pubs.acs.org.

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    This article is cited by 129 publications.

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    Cite this: J. Med. Chem. 2012, 55, 16, 7061–7079
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