Third-Generation MMP Inhibitors: Recent Advances in the Development of Highly Selective Inhibitors

Abstract

The association of matrix metalloproteinases (MMPs) with a variety of pathological states has stimulated impressive efforts over the past 20 years to develop synthetic compounds able to block potently and selectively the uncontrolled activity of these enzymes. Extremely potent inhibitors of MMPs have been developed, but in most cases these compounds act as broad-spectrum inhibitors of MMPs. Retrospective analysis suggests that the use of strong zinc-binding groups, like the hydroxamate function, to achieve potent MMP inhibition is responsible not only for the development of inhibitors displaying poor selectivity towards MMP members but also in their ability to potently block other unrelated zinc proteinases. The use of less avid zinc-binding group, like the phosphoryl group present in phosphinic peptide transition-state analogues, has led to a second generation of highly selective MMP inhibitors (MMP-12 selective inhibitors). The third generation of highly selective MMP inhibitors (MMP-13 selective inhibitors) possess no zinc-binding group and exploit the deep S₁’ cavity present in some MMPs. Past research on the development of MMP inhibitors has probably underestimated the role of flexibility in the MMP active site and its impact in accommodating different inhibitor structures. Combined use of several biophysical techniques, like nuclear magnetic resonance, X-ray crystallography and isothermal titration experiments, should greatly improve our understanding of the specific structural and dynamic features that can be exploited to obtain series of inhibitors able to specifically block each MMP validated as a therapeutic target.