Translational Development of Novel MMP Inhibitors

可以将化学实验室的发现快速转化为临床应用的转化研究 对发现新的化疗药物至关重要。这份提案描述了一个既定的 合成化学研究小组、计算化学/生物物理学之间的合作努力 研究小组和一个心脏病研究小组开发一类新的基质金属蛋白酶抑制剂 (MPIs)并在临床相关的心脏病动物模型中研究这些化合物。矩阵 金属蛋白酶(MMPs)是一类重要的水解酶，参与组织重建和细胞周期调控。 与许多疾病有关，包括心血管疾病、关节炎和癌症。这项研究 这里描述的计划代表将解决基质金属蛋白酶抑制剂设计的一系列协调一致的实验， 在已经进行的高度跨学科、协作的努力下进行综合和评价。 初步结果表明，几种新型的螯合剂对基质金属蛋白酶活性的抑制程度比 目前所研究的大多数MPIs中使用的是螯合部分(异羟肟酸)。新材料的设计与合成 提出了一种基于机理选择锌结合基团(ZBGs)的基质金属蛋白酶抑制剂。小说 将开发的MPI化合物最终将接受测试，以确定其改善后处理结果的能力 心肌梗死会改变心脏的结构和功能。因此，这项建议的主要目标是 通过使用一种全面的生物无机方法开发新型基质金属蛋白酶抑制剂 允许从机理上阐明抑制剂-金属蛋白的相互作用，并翻译基本的 从合理的药物设计到使用心脏病模型的临床前研究的发现。具体目标 这项研究计划的主要内容包括： 1.利用模型化合物确定新的MPIs抑制活性的分子机制。 2.基于改进的锌结合基团(ZBGs)的新型MPI的合成和评价。 3.用大鼠离体心标本评价新型MPI。 4.观察MPIs对在体脑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.