2. Academic Validation
  3. Arylsulfonamide inhibitors of aggrecanases as potential therapeutic agents for osteoarthritis: synthesis and biological evaluation

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

  • Eur J Med Chem. 2013 Apr:62:379-94. doi: 10.1016/j.ejmech.2012.12.058.
Elisa Nuti 1,  Salvatore Santamaria,  Francesca Casalini,  Kazuhiro Yamamoto,  Luciana Marinelli,  Valeria La Pietra,  Ettore Novellino,  Elisabetta Orlandini,  Susanna Nencetti,  Anna Maria Marini,  Silvia Salerno,  Sabrina Taliani,  Federico Da Settimo,  Hideaki Nagase,  Armando Rossello
Affiliations

Affiliation

  • 1 Dipartimento di Farmacia, Università di Pisa, via Bonanno 6, 56126 Pisa, Italy.
PMID: 23376997 DOI: 10.1016/j.ejmech.2012.12.058
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.

Figures