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

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• 作者：Elisa Nuti^a ; ¹ ; Salvatore Santamaria^b ; ^c ; ¹ ; Francesca Casalini^a ; Kazuhiro Yamamoto^c ; Luciana Marinelli^d ; Valeria La Pietra^d ; Ettore Novellino^d ; Elisabetta Orlandini^a ; Susanna Nencetti^a ; Anna Maria Marini^a ; Silvia Salerno^a ; Sabrina Taliani^a ; Federico Da Settimo^a ; Hideaki Nagase^b ; ^c ; Armando Rossello^a ; ^{aros@farm.unipi.it}
• 关键词：ADAMTS-5 ; ADAMTS-4 ; Aggrecanase inhibitors ; Arylsulfonamido-based hydroxamates ; Osteoarthritis
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：April, 2013
• 年：2013
• 卷：62
• 期：Complete
• 页码：379-394
• 全文大小：1303 K

文摘

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.