Small Molecule Therapeutics for Myocardial Ischemia

描述(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功能衰竭。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具有直接保护作用，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因许多后勤问题而变得复杂。利用一个包括噬菌体展示、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，我们已经鉴定了两个不同的化学类别的SF/HGF样小分子。成员化合物的体外筛选导致了两个不同的候选铅，每个化学类别一个。第一阶段研究表明，这两个候选者具有显著的保护作用。在这个翻译的第二阶段计划中，我们将首先在活体心肌缺血再灌注损伤的啮齿动物模型中对我们的两个候选小分子进行深入的比较。从AIM 1研究中选出的单一候选药物将进入AIM 2和AIMS 3，这两项研究包括临床相关心肌缺血损伤模型的疗效研究。在单独资金的支持下，一套全面的研究已经在进行中，以表征我们的SF/HGF模拟物的药代动力学、生物分布、急性安全性和安全性药理学概况，这些研究的初步结果非常令人鼓舞。连同这些正在进行的监管研究，拟议的疗效研究将提供足够的信息，向食品和药物管理局(FDA)提交研究性新药(IND)申请，以启动使用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。一种具有心脏保护作用的小分子生长因子疗法具有巨大的临床益处。

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.