Translational Development of Novel MMP Inhibitors

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Translational research that can rapidly transmit discoveries in the chemical laboratory to clinical application are critically important to the discovery of new chemotherapeutics. This proposal describes an established collaborative effort between a synthetic chemistry research group, a computationalchemistry/biophysics research group, and a cardiology research group to develop a new class of matrix metalloproteinase inhibitors (MPIs) and to study these compounds in clinically relevant animal models of heart disease. Matrix metalloproteinases (MMPs) are an important class of hydrolyticenzymes involvedin tissue restructuring and are implicated in a number of illnesses including cardiovascular disease, arthritis, and cancer. The research plan described herein represents a concerted series of experiments that will address MMP inhibitor design, synthesis, and evaluation under a highly interdisciplinary, collaborative effort that is already underway. Preliminary results show that several novel chelators inhibit MMP activity to a greater extent then the chelating moiety (hydroxamic acid) used in most MPIs studied to date. The design and synthesis of new MMP inhibitorsderived from mechanism-based selection of zinc-binding groups (ZBGs) is proposed. Novel MPI compounds to be developed will ultimately be tested for their ability to improve the outcome of post- myocardial infarction changes in heart structure and function. Thus, the major objective of this proposal is to develop novel matrix metalloproteinase inhibitors by using a comprehensive bioinorganic approach that allows for the mechanistic elucidation of inhibitor-metalloprotein interactions and to translate basic discoveries in rational drug design to preclinical research using models of heart disease. The specific goals of this research program are: 1. To identify the molecular mechanisms of inhibitory activity of new MPIs using model complexes. 2. To synthesize and evaluate novelMPIs based on improved zinc-binding groups (ZBGs). 3. To evaluate novel MPIs using isolated working rat heart preparations. 4. To examine the effects of MPIs on in vivo ischemia reperfusion injury.