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Aggrecanases, in particular aggrecanase-2 (ADAMTS-5), are considered the principal proteases responsible for aggrecan degradation in osteoarthritis. For this reason, considerable effort has been put on the discovery and development of aggrecanase inhibitors able to slow down or halt the progression of osteoarthritis. We report herein the synthesis and biological evaluation of a series of arylsulfonamido-based hydroxamates as aggrecanase inhibitors. Compound 18 was found to have a nanomolar activity for ADAMTS-5, ADAMTS-4 and MMP-13 and high selectivity over MMP-1 and MMP-14. Furthermore, this compound proved to be effective in blocking ex vivo cartilage degradation without having effect on cell cytotoxicity.

Type

Journal article

Journal

European journal of medicinal chemistry

Publication Date

04/2013

Volume

62

Pages

379 - 394

Addresses

Dipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.

Keywords

Humans, Osteoarthritis, Sulfonamides, Matrix Metalloproteinases, Procollagen N-Endopeptidase, Protease Inhibitors, Molecular Structure, Structure-Activity Relationship, Dose-Response Relationship, Drug, Models, Molecular, ADAM Proteins, Matrix Metalloproteinase Inhibitors