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

Tommasi, Ruben and Weiler, Sven and Mc Quire, Leslie and Rogel, Olivier and Chambers, Mark and Clark, Kirk and Doughty, John and Fang James, - and Ganu, Vishwas and Goldberg, Ronald and Goldstein, Robert and Lavoie, Stacey and Grob, Jonathan and Kulathila, Raviraj and Macchia, William and Melton, Richard and Springer, Clayton and Walker, Marc and Zhang, Jing and 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

Abstract

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
URI: https://oak.novartis.com/id/eprint/4983

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