Small Molecule Therapeutics for Myocardial Ischemia

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，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，散点因子/肝细胞生长因子对心肌细胞有直接的保护作用，可能用于缺血心肌的抢救。然而，以基因或蛋白质治疗的形式使用这种生长因子的可行性受到许多后勤问题的影响。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在内的产品发现引擎，我们已经确定了SF/ hgf样小分子的两种不同的化学类别。成员化合物的体外筛选导致两个不同的主要候选人，一个来自每个化学类。I期研究表明这两种候选物具有显著的保护作用。在这个转化II期项目中，我们将首先在啮齿动物体内心肌缺血-再灌注损伤模型中对我们的两种小分子候选物进行深入比较。Aim 1研究中出现的单一先导候选药物将进入Aims 2和Aims 3，其中包括临床相关心肌缺血损伤模型的疗效研究。在独立资金的支持下，一系列全面的研究已经在进行中，以表征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，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，拟议的功效研究将提供足够的信息，向食品和药物管理局（FDA）提交新药研究（IND）申请，以启动SF/HGF模拟物的临床试验。

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.