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 arylsulfonamidobased 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.

Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: Synthesis and biological evaluation.

NUTI, ELISA;ORLANDINI, ELISABETTA;NENCETTI, SUSANNA;MARINI, ANNA MARIA;SALERNO, SILVIA;TALIANI, SABRINA;DA SETTIMO PASSETTI, FEDERICO;ROSSELLO, ARMANDO
2013

Abstract

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 arylsulfonamidobased 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.
Nuti, Elisa; Santamaria, S; Casalini, F; Yamamoto, K; Marinelli, L; La Pietra, V; Novellino, E; Orlandini, Elisabetta; Nencetti, Susanna; Marini, ANNA MARIA; Salerno, Silvia; Taliani, Sabrina; DA SETTIMO PASSETTI, Federico; Nagase, H; Rossello, Armando
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/200154
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