Translational Development of Novel MMP Inhibitors

描述（由申请人提供）：转化研究可以快速将化学实验室的发现转化为临床应用，对于发现新的化疗药物至关重要。该提案描述了合成化学研究组、计算化学/生物物理学研究组和心脏病学研究组之间建立的合作努力，以开发一类新的基质金属蛋白酶抑制剂（MPI），并在临床相关的心脏病动物模型中研究这些化合物。基质金属蛋白酶（MMP）是一类重要的参与组织重建的水解酶，并且与包括心血管疾病、关节炎和癌症在内的许多疾病有关。本文所述的研究计划代表了一系列协调一致的实验，这些实验将在高度跨学科的合作努力下解决MMP抑制剂的设计，合成和评估。初步结果表明，几种新型螯合剂抑制MMP活性的程度更大，然后在大多数MPI研究的日期使用的螯合部分（异羟肟酸）。提出了基于锌结合基团（ZBG）的机制选择的新型MMP抑制剂的设计和合成。待开发的新型MPI化合物最终将测试其改善心肌梗死后心脏结构和功能变化的结果的能力。因此，该提案的主要目标是通过使用全面的生物无机方法开发新型基质金属蛋白酶抑制剂，该方法允许对基质金属蛋白酶-金属蛋白相互作用的机制进行阐明，并将合理药物设计中的基本发现转化为使用心脏病模型的临床前研究。本课题研究的具体目标是：1.使用模型复合物鉴定新MPI抑制活性的分子机制。2.合成和评价基于改进的锌结合基团（ZBG）的新型MPI。3.使用离体工作大鼠心脏制备物评价新型MPI。4.目的：研究MPI对在体缺血再灌注损伤的影响。

DESCRIPTION (provided by applicant): 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 computational chemistry/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 hydrolytic enzymes involved in 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 inhibitors derived 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 novel MPIs 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.