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 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.
Johnson
Adam R
AR
Department of Inflammation Molecular Sciences, Pfizer Global Research and Development, Ann Arbor, Michigan 48105, USA. adam.johnson@pfizer.com
Pavlovsky
Alexander G
AG
Ortwine
Daniel F
DF
Prior
Faith
F
Man
Chiu-Fai
CF
Bornemeier
Dirk A
DA
Banotai
Craig A
CA
Mueller
W Thomas
WT
McConnell
Patrick
P
Yan
Chunhong
C
Baragi
Vijay
V
Lesch
Charles
C
Roark
W Howard
WH
Wilson
Michael
M
Datta
Kaushik
K
Guzman
Roberto
R
Han
Hyo-Kyung
HK
Dyer
Richard D
RD
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
D004791:Enzyme Inhibitors; D007477:Ions; D003094:Collagen; D053509:Matrix Metalloproteinase 13; D015032:Zinc