At least 56
matrix metalloproteinase (
MMP) inhibitors have been pursued as clinical candidates since the late 1970's when the first
drug discovery program targeting this
enzyme family began. Some of these clinical candidates were pursued for multiple indications. However, the two primary indications that have been targeted are
cancer (24 drugs) and anti-
arthritis (27 drugs).
Cardiovascular disease was listed as an indication for 10 drugs. Forty-six
MMP inhibitors have been discontinued, 7 remain in clinical development, and only 1 (
Periostat for
periodontal disease) has been approved. Recently, negative phase II results were reported for the
MMP inhibitor PG-116800, which was being evaluated as a treatment for post-ischemic myocardial remodeling to prevent
heart failure. One major factor leading to the failure of
PG-116800 and many of the other
MMP inhibitors is the inadequate assessment of the therapeutic index, the ratio of dose required for efficacy vs. that for toxicology. This review describes the dose-limiting side effect that has hampered
MMP inhibitor development (the musculoskeletal syndrome), cardiovascular clinical
MMP inhibitor studies, a model of the therapeutic index using
marimastat, and progress towards more selective
MMP inhibitors not limited by the musculoskeletal syndrome.