Clinical potential of matrix metalloprotease inhibitors

The mature extracellular matrix (ECM) is a heterogenous substance produced by a variety of cells, mostly of mesothelial origin. The ECM serves as a tissue skeleton, a medium of communication between cells and as a barrier between the cells and the vascular system. The matrix is continuously remodelled in the living tissues. A variety of proteases, including matrix metalloproteases (MMPs), contribute to matrix destruction. These proteases are neutralised by naturally occurring inhibitors such as alpha 2-macroglobulin or tissue inhibitors of metalloproteases (TIMPs). Proteases and their inhibitors are often produced by the same cells, thus matrix remodelling is localised and strictly controlled. The MMPs are zinc-endopeptidases functioning at a neutral pH and requiring ionised calcium for activity. The extracellular matrix is an essential part of every organ and tissue type. MMPs are the key components of the system that dynamically controls the structure and function of the ECM. MMPs have been implicated in corneal disease, periodontal disease, dermatological disorders, atherosclerosis, bone and joint disorders, fibrotic disease, vascular abnormalities, malignancy and many other pathological processes. Several synthetic inhibitors of MMPs have been developed and many of them are currently in clinical trials. Compounds discussed in this article include batismastat, marimastat, BAY12-9566, AG-3340, OPB-3206, KBR-7785, KBR-8301, CDP-845 (CT-1746), metastat and AE-941 (Neovastat).