title: Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: synthesis and biological evaluation.
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 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.
authors: Dipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
authors: Elisa
authors: E
authors: Nuti
authors: Salvatore
authors: S
authors: Santamaria
authors: Francesca
authors: F
authors: Casalini
authors: Kazuhiro
authors: K
authors: Yamamoto
authors: Luciana
authors: L
authors: Marinelli
authors: Valeria
authors: V
authors: La Pietra
authors: Ettore
authors: E
authors: Novellino
authors: Elisabetta
authors: E
authors: Orlandini
authors: Susanna
authors: S
authors: Nencetti
authors: Anna Maria
authors: AM
authors: Marini
authors: Silvia
authors: S
authors: Salerno
authors: Sabrina
authors: S
authors: Taliani
authors: Federico
authors: F
authors: Da Settimo
authors: Hideaki
authors: H
authors: Nagase
authors: Armando
authors: A
authors: Rossello
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071121:ADAMTS4 Protein; D000071116:ADAMTS5 Protein; D004305:Dose-Response Relationship, Drug; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008958:Models, Molecular; D015394:Molecular Structure; D010003:Osteoarthritis / Q000188:drug therapy*; D011348:Procollagen N-Endopeptidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D013449:Sulfonamides; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D020782:Matrix Metalloproteinases; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human