Hydroxamic acids as matrix metalloproteinase inhibitors

Matrix metalloproteinases (MMPs), an increasing family of zinc- and calcium-dependent endopeptidases, are involved in both the tissue remodeling and the degradation of extracellular matrix (ECM). These enzymes have been a pharmaceutical target for over 25 years in order to develop many families of therapeutically important synthetic matrix metalloproteinase inhibitors (MMPIs) for the treatment of several serious pathologies. Although clinical trials on most of the MMPIs gave disappointing results, at least one MMPI (Periostat) has been approved by the FDA for the treatment of periodontal disease. Current research efforts on the development of selective inhibitors toward certain MMPs gave a vast number of small molecules as potent MMPIs, of which, some of the effective candidates are in their various stages of (pre)clinical trials for the treatment of various diseases such as arthritis and different cancers. The selectivity of MMPIs toward specific MMPs depends mainly on their structural templates or scaffolds and the variations in their substituents. Thus, the combination of traditional, mechanism-based, and structural-based approaches may help for the future development of specific MMPIs. In recent years, research focuses on the design and development of MMPIs possess a hydroxamic acid moiety, a strong Zn(II)-binding group, which leads to their high-affinity binding to the enzymic sites of the MMPs. We herein discuss the hydroxamic acid-based MMPIs with respect to their mechanism of interaction, structure-activity relationship (SAR), quantitative structure-activity relationship (QSAR), recent development, and clinical trials.