Identification of novel molecular scaffolds for the design of MMP-13 inhibitors: A first round of lead optimization

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 IC50 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.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Osteoarthritis (OA) is the leading cause of joint pain and disability in elderly patients. ► MMP-13-selective inhibitors are promising candidates in OA therapy. ► We screened the Life Chemicals database to seek for novel non-hydroxamate MMP-13 inhibitors. ► Experimental tests verified five novel leads. ► A first round of structure-based optimization on lead 1 was accomplished and led to an increase in potency of more than 5 fold.