Rational Design of New Drugs to Treat Ventricular Arrhythmias

治疗室性心律失常新药的合理设计

• 批准号: 8314794
• 负责人: JONATHAN J ABRAMSON
• 金额: $ 34.98万
• 依托单位: ELEX BIOTECH, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-21 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314794
• 关键词: Adult; Animals; Anti-Arrhythmia Agents; Arrhythmia; Blood; Cardiac Myocytes; Cardiac ablation; Cause of Death; Cessation of life; Congenital Disorders; Development; Drug Delivery Systems; Drug Design; Drug toxicity; Effectiveness; Goals; Heart; Heart Arrest; Heart failure; Homeostasis; Implantable Defibrillators; In Vitro; Laboratories; Libraries; Measures; Mediating; Metabolic; Molecular; Muscle Cells; Myocardial Ischemia; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Phase; Prevention; Property; Risk; Role; RyR2; Sarcoplasmic Reticulum; Specificity; Testing; Therapeutic; Time; Toxic effect; United States; Ventricular; Ventricular Arrhythmia; Ventricular Fibrillation; Ventricular Tachycardia; base; design; electron donor; in vivo; inhibitor/antagonist; innovation; meetings; mortality; mouse model; non-drug; novel strategies; success; sudden cardiac death

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.

描述(由申请人提供)：心脏性猝死(SCD)是一种主要的死亡原因，仅在美国每年就有30多万成年人死亡。心脏骤停和心源性心脏病是由室性心律失常引起的，特别是室颤，导致心脏无法在全身循环血液。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选择包括植入型心律转复除颤器(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，使用这些药物会增加死亡的风险。显然需要一种新的创新方法来开发更有效、更具体和更安全的抗心律失常药物来治疗和防止室性心动过速。鉴于RyR2在控制钙稳态方面的突出作用，调节RyR2稳定性和门控的药物策略已显示出作为心律失常治疗的巨大前景。不幸的是，目前用于治疗心律失常的许多药物在作用上都是非特异性的。该方案中采用的方法包括生成一个具有增强的电子给体性质的新的RyR2抑制剂的小型库。这种方法是基于我们的观察结果，即靶向RyR2的药物的电子供体性质是这些新分子有效性的主要决定因素。到目前为止的进展表明，具有增强的电子供体性质的新药可以作为RyR2的高效抑制剂，并在致心律失常的小鼠模型中作为有效的心律失常抑制剂。本项目的具体目标如下：1)设计和合成具有增强电子给体性质的新型RyR2抑制剂。2)从分子水平、细胞水平和动物整体水平评价这些化合物作为RyR2电子供体和RyR2抑制剂的有效性。在细胞和整个动物水平上确定它们在正常化钙离子稳态和减少心律失常方面的效力，并确定这些新化合物的特异性。3)评价这些新药对心肌细胞的毒性作用。进行体内和体外毒性研究，并测定这些新药的代谢稳定性。第一阶段的成功将根据本研究开发的新药的效力进行评估。ELEX生物技术公司第一阶段的目标是开发一组新药，这些新药在正常化心室肌细胞钙稳态和减少心律失常方面的效果比我们的起始化合物高100至1000倍。 公共卫生相关性：心律失常引起的心脏骤停和心源性猝死是美国和世界的主要死亡原因。现有的药物往往只有轻微的效果，而且相对非特异性。为了满足对有效疗法的迫切需求，ELEX生物技术公司将通过一种新的药物设计方法来创造治疗室性心律失常的新的更有效的药物。