Rational Design of New Drugs to Treat Ventricular Arrhythmias

描述（由申请人提供）：心源性猝死（SCD）是导致死亡的主要原因，仅在美国每年就有超过30万成年人死亡。心脏骤停和SCD是由室性心律失常引起的，特别是心室颤动，这导致心脏无法将血液循环到全身。大约50%的心力衰竭患者死于室性心律失常。终止或抑制室性心动过速发作的治疗方案包括植入式心律转复除颤器（ICD）、导管消融和抗心律失常药物。抗心律失常药物治疗室性心动过速的疗效仍然不理想，在某些情况下，它们的使用导致死亡风险增加。显然需要一种新的创新方法来开发更有效、更特异和更安全的抗心律失常药物来治疗和预防室性心动过速。考虑到RyR2在Ca2+稳态控制中的重要作用，调节RyR2稳定性和门控的药理学策略已经显示出作为心律失常治疗的巨大希望。不幸的是，目前用于治疗心律失常的许多药物在其作用上是非特异性的。本提案中采用的方法包括生成一个具有增强电子供体性质的新RyR2抑制剂的小库。这种方法是基于我们的观察，即针对RyR2的药物的电子供体特性是这些新分子有效性的主要决定因素。迄今为止的进展表明，在致心律失常小鼠模型中，具有增强电子供体特性的新药可作为RyR2的高效抑制剂和心律失常的有效抑制剂。本课题的具体目的如下：1)设计合成具有增强电子给体性能的新型RyR2抑制剂。2)在分子、细胞和全动物水平上评价这些化合物作为电子给体和RyR2抑制剂的效力。确定其在细胞和全动物水平上正常Ca2+稳态和减少心律失常的效力，并确定这些新化合物的特异性。3)评价这些新药对心室肌细胞的毒性。开展体内和体外毒性研究，确定这些新药的代谢稳定性。第一阶段的成功将根据本研究中开发的新药的效力来评估。ELEX生物技术公司在第一阶段的目标是开发一组新药，这些新药在恢复心室肌细胞Ca2+稳态和减少心律失常方面的效果比我们的初始化合物高100到1000倍。

DESCRIPTION (provided by applicant): Sudden cardiac death (SCD) is a major cause of death, responsible for greater than 300,000 adult deaths per year in the United States alone. Cardiac arrest and SCD are caused by ventricular arrhythmias, in particular ventricular fibrillation, which leads to the inability of the heart to circulate blood throughout the body. Approximately 50% of patients suffering from heart failure die as a result of ventricular arrhythmias. Treatment options for the termination or suppression of episodes of ventricular tachycardia include implantable cardioverter-defibrillators (ICD), catheter ablation, and anti-arrhythmic drugs. The efficacy of anti-arrhythmic drugs for the treatment of ventricular tachycardia remains suboptimal, and in some cases their use results in an increased the risk of mortality. There is a clear need for a new innovative approach for developing more effective, specific and safer anti- arrhythmic drugs for the treatment and prevention of ventricular tachycardia. Given the prominent role of RyR2 in the control of Ca2+ homeostasis, pharmacological strategies to modulate RyR2 stability and gating have shown great promise as a therapy for cardiac arrhythmias. Unfortunately, many of the drugs presently used to treat arrhythmias are non-specific in their action. The approach taken in this proposal involves generating a small library of new RyR2 inhibitors with enhanced electron donor properties. This approach is based on our observation that the electron donor properties of drugs targeting RyR2 are prime determinants of the effectiveness of these new molecules. Progress to date demonstrates that new drugs with enhanced electron donor properties act as highly effective inhibitors of RyR2 and as effective inhibitors of arrhythmias in an arrhythmogenic mouse model. The specific aims of this project are as follows: 1) to design and synthesize new RyR2 inhibitors with enhanced electron donor properties. 2) To evaluate the potency of these compounds as electron donors, and as inhibitors of RyR2 at the molecular, cellular and whole animal level. To determine their potency in normalizing Ca2+ homeostasis and decreasing arrhythmias at the cellular, and whole animal level, and to determine the specificity of these new compounds. 3) To evaluate the toxicity of these new drugs in ventricular myocytes. To carry out in vivo and in vitro toxicity studies, and to determine the metabolic stability of these new drugs. Success in phase 1 will be evaluated on the basis of the potency of the new drugs developed in this study. The goal of ELEX Biotech in phase 1 is to develop a group of new drugs which are 100 to 1000 times more effective than our starting compounds in normalizing Ca2+ homeostasis in ventricular myocytes, and decreasing arrhythmias. PUBLIC HEALTH RELEVANCE: Cardiac Arrest and sudden cardiac death caused by arrhythmias is a major cause of death in the United States and in the world. Existing medications tend to be only mildly effective and are relatively non-specific. In order to meet the urgent need for effective therapeutics, ELEX Biotech will create new more potent medications to treat ventricular arrhythmias via a novel approach toward drug design.