Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.
Skip to main content

Osteoarthritis (OA) is the leading cause of joint pain and disability in middle-aged and elderly patients, and is characterized by progressive loss of articular cartilage. Among the various matrix metalloproteinases (MMPs), MMP-13 is specifically expressed in the cartilage of human OA patients and is not present in normal adult cartilage. Thus, MMP-13-selective inhibitors are promising candidates in osteoarthritis therapy. Recently, we designed an N-isopropoxy-arylsulfonamide-based hydroxamate inhibitor, which showed low nanomolar activity and high selectivity for MMP-13. In parallel to further studies aiming to assess the in vivo activity of our compound, we screened the Life Chemicals database through computational docking to seek for novel scaffolds as zinc-chelating non-hydroxamate inhibitors. Experimental evaluation of 20 selected candidate compounds verified five novel leads with IC(50) in the low μM range. These newly discovered inhibitors are structurally unrelated to the ones known so far and provide useful scaffolds to develop compounds with more desirable properties. Finally, a first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold.

Original publication




Journal article


European journal of medicinal chemistry

Publication Date





143 - 152


Dipartimento di Chimica Farmaceutica e Tossicologica, Università di Napoli Federico II Via D. Montesano 49, 80131 Napoli, Italy.


Humans, Protease Inhibitors, Crystallography, X-Ray, Drug Evaluation, Preclinical, Inhibitory Concentration 50, Catalytic Domain, Drug Design, User-Computer Interface, Matrix Metalloproteinase 13, Matrix Metalloproteinase Inhibitors