Thirty-six years in the clinic without an MMP inhibitor. What hath collagenase wrought?

Vertebrate collagenase was discovered in 1962, and within a few short years, several inhibitors had been identified. At one time or another, virtually every major drug company has had an MMP inhibitor program, but in 1999, there is only one such product on the market. With a potential market for lifelong therapy in rheumatoid arthritis, osteoarthritis, periodontal disease, osteoporosis, and cancer, this is certainly puzzling. The problem is that the chemistry appears to have outstripped the biology. In vitro, there are many inhibitors with nanomolar or picomolar efficacy, but in vivo efficacy in animal models does not always follow. There is also a conceptual problem regarding broad-spectrum vs. highly specific inhibitors. Designing human trials to demonstrate MMP inhibition and clinical efficacy is a daunting problem, especially if one seeks to distinguish anti-MMP activity from anti-inflammatory effect. Adult periodontal disease may be the best available human disease model for development of an MMPI.