Small Molecule Therapeutics for Myocardial Ischemia

心肌缺血的小分子治疗

• 批准号: 7157113
• 负责人: PRAKASH NARAYAN
• 金额: $ 84.49万
• 依托单位: ANGION BIOMEDICA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-11-01 至 2008-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7157113
• 关键词: biomimetics; biotechnology; comorbidity; disease /disorder model; drug screening /evaluation; heart disorder chemotherapy; hepatocyte growth factor; laboratory rat; myocardial ischemia /hypoxia; nonhuman therapy evaluation; small molecule; swine

DESCRIPTION (provided by applicant): Left untreated, myocardial ischemia can lead to cardiomyocyte death and pump failure. In fact, myocardial infarction 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, we have identified two distinct chemical classes of SF/HGF-like small molecules. In vitro screening of member compounds led to two distinct lead candidates, one from each chemical class. Phase I studies that these two candidates exert significant protective effects. In this translational Phase II program, we will first make an in- depth comparison of our two small molecule candidates in a rodent model of in vivo myocardial ischemia- reperfusion injury. The single lead candidate emerging from Aim 1 studies will be entered into Aims 2 and 3, which comprise of efficacy studies in clinically relevant models of myocardial ischemic injury. Supported by separate funding, a comprehensive set of studies to characterize the pharmacokinetic, biodistribution, acute safety and safety pharmacology profile of our SF/HGF mimetics is already underway and preliminary results from these studies are extremely encouraging. Together with these ongoing regulatory studies, the proposed efficacy studies will provide sufficient information to submit an Investigational New Drug (IND) application to the Food and Drug Administration (FDA) for initiation of a clinical trial with an SF/HGF mimetic. Myocardial infarction remains a significant cause of morbidity and mortality. A small molecule growth factor therapeutic that is cardioprotective has tremendous clinical benefit.

描述（由申请人提供）：如果不进行治疗，心肌缺血可导致心肌细胞死亡和泵衰竭。事实上，心肌梗死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。使用包括噬菌体展示，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，我们已经确定了SF/HGF样小分子的两种不同的化学类别。在体外筛选的成员化合物导致两个不同的铅候选人，一个从每个化学类。第一阶段研究表明，这两种候选药物具有显著的保护作用。在这个转化的II期计划中，我们将首先在体内心肌缺血-再灌注损伤的啮齿动物模型中对我们的两种小分子候选物进行深入比较。目标1研究中出现的单电极候选电极将进入目标2和3，包括在心肌缺血性损伤的临床相关模型中进行的疗效研究。在单独资金的支持下，一系列表征我们的SF/HGF模拟物的药代动力学、生物分布、急性安全性和安全药理学特征的综合研究已经在进行中，这些研究的初步结果非常令人鼓舞。与这些正在进行的监管研究一起，拟定的疗效研究将提供足够的信息，以向美国食品药品监督管理局（FDA）提交研究性新药（IND）申请，启动SF/HGF模拟物的临床试验。 心肌梗死仍然是发病率和死亡率的重要原因。一种小分子生长因子治疗，是心脏保护有巨大的临床效益。