Excessive or poorly regulated
matrix metalloproteinase (
MMP) activity has been implicated as a pathogenic factor in a range of diseases where the extracellular matrix is degraded or remodelled. Synthetic, potent, low molecular weight
MMP inhibitors (MMPIs) have been developed and, over the past five years, these agents have begun clinical testing in patients with
cancer,
rheumatoid arthritis,
osteoarthritis and acute
macular degeneration. The past year has seen a number of disappointments with the halting of clinical trials of
Ro 32-3555 in patients with
rheumatoid arthritis and of
BAY 12-9566 in patients with
cancer. There have, however, been some successes with perhaps the clearest indication of efficacy being seen in the results of a Phase III trial of
marimastat in patients with advanced
gastric cancer. Clinical trials are continuing with
marimastat and other MMPIs, including
prinomastat, solimastat, BMS 275291,
metastat and
neovastat. Results from these trials are expected in the next two years and it is likely that clinical trials with MMPIs will begin in patients with other diseases where
MMPs are believed to be involved, such as restenosis, cerebral haemorrhage and
multiple sclerosis. Future research is likely to focus on the identification of specific
MMP targets in different diseases, both in order to improve efficacy and to reduce the musculoskeletal side effect profile that has characterised several of the first generation oral MMPIs.