Translational Development of Novel MMP Inhibitors

转化研究，可以迅速将化学实验室的发现转化为临床应用 对发现新的化疗药物至关重要。该提案描述了一个既定的 一个合成化学研究小组，一个计算化学/生物物理学 研究小组和心脏病学研究小组开发一种新的基质金属蛋白酶抑制剂 （MPI），并在心脏病的临床相关动物模型中研究这些化合物。矩阵 金属蛋白酶（MMPs）是一类重要的参与组织重建的水解酶， 与许多疾病有关，包括心血管疾病、关节炎和癌症。研究 本文所述的计划代表了一系列协调一致的实验， 在高度跨学科的协作努力下进行的综合和评估工作已经在进行之中。 初步结果表明，几种新的螯合剂抑制MMP活性的程度大于 螯合部分（异羟肟酸）用于迄今为止研究的大多数MPI。新的设计和合成 提出了基于锌结合基团（ZBG）的机制选择的MMP配体。小说 将开发的MPI化合物最终将测试其改善术后结局的能力。 心肌梗死改变心脏结构和功能。因此，这项建议的主要目的是 通过使用综合的生物无机方法开发新型基质金属蛋白酶抑制剂， 允许阐明通道-金属蛋白相互作用的机制，并翻译基本的 从合理药物设计的发现到使用心脏病模型的临床前研究。的具体目标 该研究计划的主要内容是： 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。

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.