title: Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects.
abstract: Matrix metalloproteinase-13 (MMP13) is a Zn(2+)-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.
authors.affiliation: Department of Inflammation Molecular Sciences, Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA. adam.johnson@pfizer.com
authors.forename: Adam R
authors.initials: AR
authors.lastname: Johnson
authors.forename: Alexander G
authors.initials: AG
authors.lastname: Pavlovsky
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Ortwine
authors.forename: Faith
authors.initials: F
authors.lastname: Prior
authors.forename: Chiu-Fai
authors.initials: CF
authors.lastname: Man
authors.forename: Dirk A
authors.initials: DA
authors.lastname: Bornemeier
authors.forename: Craig A
authors.initials: CA
authors.lastname: Banotai
authors.forename: W Thomas
authors.initials: WT
authors.lastname: Mueller
authors.forename: Patrick
authors.initials: P
authors.lastname: McConnell
authors.forename: Chunhong
authors.initials: C
authors.lastname: Yan
authors.forename: Vijay
authors.initials: V
authors.lastname: Baragi
authors.forename: Charles
authors.initials: C
authors.lastname: Lesch
authors.forename: W Howard
authors.initials: WH
authors.lastname: Roark
authors.forename: Michael
authors.initials: M
authors.lastname: Wilson
authors.forename: Kaushik
authors.initials: K
authors.lastname: Datta
authors.forename: Roberto
authors.initials: R
authors.lastname: Guzman
authors.forename: Hyo-Kyung
authors.initials: HK
authors.lastname: Han
authors.forename: Richard D
authors.initials: RD
authors.lastname: Dyer
mesh_terms: D000818:Animals; D002356:Cartilage / Q000378:metabolism*; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007477:Ions; D007592:Joint Diseases / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D008954:Models, Biological; D008956:Models, Chemical; D008958:Models, Molecular; D011817:Rabbits; D051381:Rats; D015032:Zinc / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D007477:Ions; D003094:Collagen; D053509:Matrix Metalloproteinase 13; D015032:Zinc