Discovery and Characterization of a Novel Inhibitor of Matrix Metalloprotease-13 That Reduces Cartilage Damage in Vivo without Joint Fibroplasia Side Effects

Matrix metalloproteinase-13 (MMP13) is a Zn2+-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However,...

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Bibliographic Details
Published in:The Journal of biological chemistry 2007-09, Vol.282 (38), p.27781-27791
Main Authors: Johnson, Adam R., Pavlovsky, Alexander G., Ortwine, Daniel F., Prior, Faith, Man, Chiu-Fai, Bornemeier, Dirk A., Banotai, Craig A., Mueller, W. Thomas, McConnell, Patrick, Yan, Chunhong, Baragi, Vijay, Lesch, Charles, Roark, W. Howard, Wilson, Michael, Datta, Kaushik, Guzman, Roberto, Han, Hyo-Kyung, Dyer, Richard D.
Format: Article
Language:English
Subjects:
Animals
Cartilage - metabolism
Collagen - chemistry
Collagen - metabolism
Crystallography, X-Ray
Enzyme Inhibitors - pharmacology
Humans
Ions
Joint Diseases - metabolism
Matrix Metalloproteinase 13 - chemistry
Matrix Metalloproteinase 13 - metabolism
Matrix Metalloproteinase 13 - physiology
Models, Biological
Models, Chemical
Models, Molecular
Rabbits
Rats
Zinc - chemistry
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Summary:Matrix metalloproteinase-13 (MMP13) is a Zn2+-dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structure-based drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients.
ISSN:0021-9258
1083-351X
1083-351X
DOI:10.1074/jbc.M703286200