Translational Development of Novel MMP Inhibitors

描述(由申请人提供)：能够迅速将化学实验室的发现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。该提案描述了合成化学研究小组、计算化学/生物物理研究小组和心脏病学研究小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(MPIs)，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(MMPs)是一类重要的水解酶，参与组织结构重建，与心血管疾病、关节炎和癌症等多种疾病有关。这里描述的研究计划代表了一系列协调一致的实验，这些实验将在已经进行的高度跨学科的协作努力下解决基质金属蛋白酶抑制剂的设计、合成和评估问题。初步结果表明，几种新型的螯合剂比目前所研究的大多数MPI中使用的螯合部分(异羟肟酸)对基质金属蛋白酶活性的抑制程度更大。提出了基于锌结合基团(ZBGs)机理选择的新型基质金属蛋白酶抑制剂的设计和合成方法。将开发的新型MPI化合物最终将被测试其改善心肌梗死后心脏结构和功能变化的能力。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来开发新的基质金属蛋白酶抑制剂，该方法允许从机理上阐明抑制剂-金属蛋白相互作用，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。本研究的具体目标是：1.利用模型络合物确定新的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。

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.