Abstract
The pursuit of matrix metalloproteinase (MMP) inhibitors began in earnest over three decades ago. Initial clinical trials were disappointing, resulting in a negative view of MMPs as therapeutic targets. As a better understanding of MMP biology and inhibitor pharmacokinetic properties emerged, it became clear that initial MMP inhibitor clinical trials were held prematurely. Further complicating matters were problematic conclusions drawn from animal model studies. The most recent generation of MMP inhibitors have desirable selectivities and improved pharmacokinetics, resulting in improved toxicity profiles. Application of selective MMP inhibitors led to the conclusion that MMP-2, MMP-9, MMP-13, and MT1-MMP are not involved in musculoskeletal syndrome, a common side effect observed with broad spectrum MMP inhibitors. Specific activities within a single MMP can now be inhibited. Better definition of the roles of MMPs in immunological responses and inflammation will help inform clinic trials, and multiple studies indicate that modulating MMP activity can improve immunotherapy. There is a U.S. Food and Drug Administration (FDA)-approved MMP inhibitor for periodontal disease, and several MMP inhibitors are in clinic trials, targeting a variety of maladies including gastric cancer, diabetic foot ulcers, and multiple sclerosis. It is clearly time to move on from the dogma of viewing MMP inhibition as intractable.
Highlights
Activities of the matrix metalloproteinase (MMP) family (Figure 1) have long been correlated to disease initiation and progression [1,2,3,4,5,6]
These results suggest that nonspecific inhibition of metalloproteinases may explain the toxicity observed with MMP inhibitors in clinical trials [33,46,47]
We have reported that phosphinic triple-helical peptides (THPs) behave as effective transition state analog inhibitors of collagenolytic
Summary
Activities of the matrix metalloproteinase (MMP) family (Figure 1) have long been correlated to disease initiation and progression [1,2,3,4,5,6]. The poor selectivity of broad spectrum inhibitors led to limited beneficial effect and did not justify the further pursuit of clinical trials [18]. As the role of MMPs may change from detrimental to beneficial, or vice versa, during the proposed to play role in MSS development were MMP-1 [35], MMP-2 [36], MMP-9 [37], MT1-MMP [38], and course of disease, the mechanism and/or substrate profile of MMPs needs to be clearly identified. Clinical trials using broad spectrum inhibitors often led to severe side effects and had MMP inhibition results in fibroproliferation affecting the patellar tendon and other intra- and periarticular connective tissues in rats, mimicking MSS
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
