Matrix Metalloproteinase Inhibitors

Abstract

Matrix metalloproteinases (MMPs) play an important role in tissue remodelling associated with various physiological and pathological processes, such as morphogenesis, angiogenesis, tissue repair, arthritis, chronic heart failure, chronic obstructive pulmonary disease, chronic inflammation and cancer metastasis. As a result, MMPs are considered to be viable drug targets in the therapy of these diseases. Despite the high therapeutic potential of MMP inhibitors (MMPIs), all clinical trials have failed to date, except for doxycycline for periodontal disease. This can be attributed to (i) poor selectivity of the MMPIs, (ii) poor target validation for the targeted therapy and (iii) poorly defined predictive preclinical animal models for safety and efficacy. Lessons from previous failures, such as recent discoveries of oxidative/nitrosative activation and phosphorylation of MMPs, as well as novel non-matrix related intra- and extracellular targets of MMP, give new hope for MMPI development for both chronic and acute diseases. In this article we critically review the major structural determinants of the selectivity and the milestones of past design efforts of MMPIs where 2-/3-dimensional structure-based methods were intensively applied. We also analyse the in vitro screening and preclinical/clinical pharmacology approaches, with particular emphasis on drawing conclusions on how to overcome efficacy and safety problems through better target validation and design of preclinical studies.

Minocycline is More Potent Than Tetracycline and Doxycycline in Inhibiting MMP-9 in Vitro

“…Tetracyclines, EDTA, hydroxamic acid derivatives (marimastat and batimastat), 1, 10-phenanthroline, and pyrimidinetrione derivatives have been studied as MMP inhibitors (9).…”

Exploring the functional space of thiiranes as gelatinase inhibitors using click chemistry

“…27,28 Accordingly, the incorporation of structural segments to attain sub-type selectivity is a focus of every current medicinal chemistry effort directed toward the inhibition of one of these proteases. 29,30 Toward this objective, the mechanism-based thiirane inhibitor 1 is remarkable. It would appear that only members of the gelatinase sub-family of the MMPs (MMP-2 and MMP-9) are able to efficiently use their active site-glutamate for the deprotonation-dependent opening of the thiirane to liberate the caged thiolate as a stable ligand for the catalytic zinc atom.…”

MMP-9 genetic polymorphism may confer susceptibility to COPD

“…MMP-9 is synthesized as preproenzyme consisting of 707-amino acid residues and is the most complex member of the MMP family (Folseraas and Karlsen, 2011;Liu et al, 2012). Several studies have described the important roles MMPs play in various pathological and physiological processes, such as tissue repair, COPD, angiogenesis, and chronic inflammation (Dormán et al, 2010;Wu et al, 2012). However, the correlation between genetic polymorphisms of MMPs and susceptibility to COPD remains controversial (Schirmer et al, 2009;Cheng et al, 2009).…”