Matrix metalloproteinase inhibitors in rheumatic diseases.
The rheumatic diseases continue to represent a significant healthcare burden in the 21st century. However, despite the best standard of care and recent therapeutic advances it is still not possible to consistently prevent the progressive joint destruction that leads to chronic disability. In rheumatoid arthritis and osteoarthritis this progressive cartilage and bone destruction is considered to be driven by an excess of the matrix metalloproteinase (MMP) enzymes. Consequently, a great number of potent small molecule MMP inhibitors have been examined. Several MMP inhibitors have entered clinical trials as a result of impressive data in animal models, although only one MMP inhibitor, Ro32-3555 (Trocade), a collagenase selective inhibitor, has been fully tested in the clinic, but it did not prevent progression of joint damage in patients with rheumatoid arthritis. The key stages and challenges associated with the development of an MMP inhibitor in the rheumatic diseases are presented below with particular reference to Trocade. It is concluded that the future success of MMP inhibitors necessitates a greater understanding of the joint destructive process and it is hoped that their development may be accompanied with clearer, more practical, outcome measures to test these drugs for, what remains, an unmet medical need.
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Department of Clinical Science, Roche Products Ltd, Welwyn Garden City, Hertfordshire, UK. david.close@roche.com
D000818:Animals; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D016032:Randomized Controlled Trials as Topic; D012216:Rheumatic Diseases / Q000188:drug therapy* / Q000473:pathology; D016896:Treatment Outcome
D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D061965:Matrix Metalloproteinase Inhibitors; C106997:Ro 32-3555