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Potent and Selective 2-Naphthylsulfonamide Substituted Hydroxamic Acid Inhibitors of Matrix Metalloproteinase-13

Tommasi, Ruben, Weiler, Sven, Mc Quire, Leslie, Rogel, Olivier, Chambers, Mark, Clark, Kirk, Doughty, John, Fang James, -, Ganu, Vishwas, Goldberg, Ronald, Goldstein, Robert, Lavoie, Stacey, Grob, Jonathan, Kulathila, Raviraj, Macchia, William, Melton, Richard, Springer, Clayton, Walker, Marc, Zhang, Jing, Zhu, Lijuan and Shultz, Michael (2011) Potent and Selective 2-Naphthylsulfonamide Substituted Hydroxamic Acid Inhibitors of Matrix Metalloproteinase-13. Bioorganic and Medicinal Chemistry Letters, 21 (21). pp. 6440-6445. ISSN 0960-894X


The matrix metalloproteinase enzyme MMP-13 plays a key role in the degradation of type II collagen in cartilage and bone in osteoarthritis (OA). An effective MMP-13 inhibitor would provide a disease modifying therapy for the treatment of arthritis, although this goal still continues to elude the pharmaceutical industry due to issues with safety. Our efforts have resulted in the discovery of a series of hydroxamic acid inhibitors of MMP-13 that do not significantly inhibit MMP-2 (gelatinase-1). MMP-2 has been implicated in the musculoskeletal side effects resulting from pan-MMP inhibition due to findings from spontaneously occurring human MMP-2 deletions. Analysis of the SAR of hundreds of previously prepared hydroxamate based MMP inhibitors lead us to 2-naphthylsulfonamide substituted hydroxamates which exhibited modest selectivity for MMP-13 versus MMP-2. This paper describes the lead optimization of 1 and identification of inhibitors exhibiting >100-fold selectivity for MMP-13 over MMP-2.

Item Type: Article
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Keywords: MMP, Hydroxamic Acid
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15


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