Small Molecule Therapeutics for Myocardial Ischemia

心肌缺血的小分子治疗

• 批准号: 6935538
• 负责人: PRAKASH NARAYAN
• 金额: $ 22.58万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2006-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6935538
• 关键词: animal tissue; biomimetics; chemical registry /resource; combinatorial chemistry; drug discovery /isolation; drug screening /evaluation; heart disorder chemotherapy; hepatocyte growth factor; laboratory rat; myocardial ischemia /hypoxia; nonhuman therapy evaluation; phage display; pharmacokinetics; proteomics; small molecule

DESCRIPTION (provided by applicant): Left untreated, myocardial ischemia can lead to cardiomyocte death and pump failure. In fact, ischemic heart disease is a significant cause of morbidity and mortality in the U.S. Recent evidence suggests that scatter factor / hepatocyte growth factor, exerts direct protective effects on cardiac myocytes and can potentially be used for salvage of the ischemic myocardium. However the feasibility of using this growth factor in the form of gene or protein therapy is compounded by numerous logistical issues. Using a product discovery engine comprising phage display, 3-dimensional molecular modeling, protein chemistry and preclinical biology, Angion successfully identified an organic small molecule mimetic of scatter factor. We have since identified a library of compounds based on the Refanalin structure that are potential scatter factor mimetics. The present Phase I application couples a targeted proteomics approach with efficacy studies to identify a small molecule pharmacophore within this library that mimics the effects of scatter factor on the cardiac myocyte and protects against myocardial infarction. The lead candidate emerging from these studies will be submitted to in-depth Phase II studies with the ultimate objective of using a small molecule mimetic of scatter factor for salvage of the ischemic myocardium.

描述（由申请人提供）： 如果不及时治疗，心肌缺血可导致心肌细胞死亡和泵衰竭。事实上，缺血性心脏病是美国发病率和死亡率的重要原因。最近的证据表明，分散因子/肝细胞生长因子对心肌细胞发挥直接保护作用，并可能用于挽救缺血心肌。然而，以基因或蛋白质疗法的形式使用这种生长因子的可行性由于许多后勤问题而复杂化。利用包括噬菌体展示、三维分子建模、蛋白质化学和临床前生物学的产品发现引擎，Angion成功地鉴定了散射因子的有机小分子模拟物。我们已经确定了一个基于Refanalin结构的化合物库，这些化合物是潜在的散射因子模拟物。目前的I期申请将靶向蛋白质组学方法与功效研究相结合，以鉴定该文库中的小分子药效团，其模拟散射因子对心肌细胞的作用并保护免受心肌梗死。从这些研究中产生的主要候选者将被提交到深入的II期研究，最终目的是使用散射因子的小分子模拟物来挽救缺血性心肌。