Translational Development of Novel MMP Inhibitors

新型 MMP 抑制剂的转化开发

基本信息

批准号：
7162968
负责人：
SETH M COHEN
金额：
$ 36.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-01-01 至 2010-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7162968
关键词：
Active Sites Address Adverse effects Affinity Animal Model Animals Arthritis Basic Science Binding Biochemical Biological Assay Biophysics Blood Vessels Cardiac Cardiology Cardiovascular Diseases Cardiovascular Pathology Chelating Agents Class Clinical Trials Coculture Techniques Collagen Complex Computer Assisted Computing Methodologies Coronary Cultured Cells Cytolysis Development Disabled Persons Disease Drug Design Drug Kinetics Enzymes Evaluation Failure Fibroblasts Functional disorder Generations Goals Heart Heart Diseases Heart failure Human Hydroxamic Acids In Vitro Injury Ions Ischemia Laboratories Laboratory Chemicals Lead Malignant Neoplasms Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Metalloproteases Metalloproteins Metals Modeling Molecular Muscle Muscle Cells Musculoskeletal Pain Myocardial Myocardial Infarction Numbers Oral Outcome Performance Pharmaceutical Preparations Physiological reperfusion Play Preparation Purpose Rattus Recombinants Recovery Reperfusion Injury Reperfusion Therapy Research Research Personnel Role Screening procedure Series Stroke Structure Synthesis Chemistry Testing Thermodynamics Tissues Toxic effect Translating Translational Research Translations Ventricular Remodeling Vertebral column Work Zinc base chemical stability clinical application clinically relevant computational chemistry design functional group handicapping condition improved in vivo inhibitor/antagonist myocardial infarct sizing novel pre-clinical research programs research study success therapeutic target

项目摘要

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.

描述（由申请人提供）：能够将化学实验室的发现快速转化为临床应用的转化研究对于新化疗药物的发现至关重要。该提案描述了合成化学研究小组、计算化学/生物物理学研究小组和心脏病学研究小组之间建立的合作努力，以开发一类新型基质金属蛋白酶抑制剂（MPIs），并在临床相关动物模型中研究这些化合物心脏病。基质金属蛋白酶 (MMP) 是一类重要的参与组织重组的水解酶，与心血管疾病、关节炎和癌症等多种疾病有关。本文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 MMP 抑制剂的设计、合成和评估问题。初步结果表明，与迄今为止研究的大多数 MPI 中使用的螯合部分（异羟肟酸）相比，几种新型螯合剂对 MMP 活性的抑制程度更大。提出了基于锌结合基团 (ZBG) 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塞后心脏结构和功能变化结果的能力。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，该方法可以阐明抑制剂-金属蛋白相互作用的机制，并将合理药物设计的基本发现转化为使用心脏病模型的临床前研究。该研究计划的具体目标是： 1. 使用模型复合物确定新 MPI 抑制活性的分子机制。 2. 合成和评估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剂评估新型 MPI。 4.考察MPIs对体内缺血再灌注损伤的影响。