New drugs for treatment of atrial fibrillation

治疗心房颤动的新药

• 批准号: 6587508
• 负责人: Antonio E. Lacerda
• 金额: $ 37.98万
• 依托单位: CHANTEST, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-07 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6587508
• 关键词: atrial fibrillation; cardiovascular agents; cell line; combinatorial chemistry; dogs; drug design /synthesis /production; drug screening /evaluation; electrophysiology; heart electrical activity; heart pharmacology; high throughput technology; ion channel blocker; membrane channels; potassium channel

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most common cause of arrhythmias in the elderly; it has an incidence of more than 5 percent in people > 69 years of age. At present, there is no satisfactory treatment of this disease. The ChanTest Phase I SBIR was directed towards the discovery of novel drugs for this disease and in these experiments, the investigators identified a substituted piperidine compound that promises to be an effective antiarrhythmic agent. They found that this drug blocks the hERG/IKr current at low nanomolar concentrations, yet does not prolong the action potential duration in canine Purkinje fibers at micromolar concentrations as might be expected. The investigators hypothesized that the drug also blocked cardiac Na and Ca currents at nanomolar concentrations and, as a result, the hERG/IKr block was offset and there was no change in action potential duration. The drug had another useful characteristic, namely the forward use-dependence of a drug that is most effective at faster heart rates. This drug was in clinical trials in the late 1970s as an antidepressant and although it was safe, did not have the desired efficacy. It is now in clinical trials as a treatment for substance abuse. In neither of these trials were proarrhythmic tendencies noted and the ECGs in both sets of trials were unaffected. Because its properties are so favorable, ChanTest has filed a use patent on the drug for treatment of cardiac arrhythmias in general, and AF in particular. Given its very high affinity for hERG, a radioactive derivative can be used in high throughput displacement studies to test for non-cardiac drugs that may bind to hERG. Identifications of such drugs are of considerable importance for safety pharmacology. The specific aims of this proposal are to: 1) complete in vitro tests of the effects of the drug on other cardiac membrane currents ITo, IKs and IK1; 2) test the drug's efficacy in animal models of AF; 3) test the drug's safety in the cardiac muscle wedge preparation that is presently the best predictor of the potentially lethal ventricular arrhythmia torsade de pointes (TdP); and 4) characterize the drug congeners as tools for HTS displacement studies of drugs that bind hERG. After the drug passes the hurdles of the specific aims, ChanTest will file a 355(b)(2) NDA application with the FDA to go forward with the Phase II and III clinical trials. ChanTest believes that this drug will offer great relief to the many people who are debilitated by atrial fibrillation.

描述（由申请人提供）：心房颤动（AF）是老年人心律失常的最常见原因;在69岁以上的人群中，其发病率超过5%。目前，这种疾病还没有令人满意的治疗方法。ChanTest I期SBIR旨在发现治疗这种疾病的新药，在这些实验中，研究人员发现了一种取代的哌啶化合物，有望成为一种有效的抗肿瘤药物。他们发现，这种药物在低纳摩尔浓度下阻断hERG/IKr电流，但在微摩尔浓度下不会延长犬浦肯野纤维的动作电位时程。研究者假设药物在纳摩尔浓度下也阻断心脏Na和Ca电流，因此，hERG/IKr阻滞被抵消，动作电位时程没有变化。该药物还有另一个有用的特性，即药物的前向使用依赖性，在心率加快时最有效。这种药物在20世纪70年代末作为抗抑郁药进行了临床试验，虽然它是安全的，但没有达到预期的疗效。它现在正在临床试验中作为药物滥用的治疗方法。在这两项试验中均未观察到促排卵趋势，两组试验中的ECG均未受影响。因为它的特性是如此有利，ChanTest已经申请了一项用于治疗心律失常的药物的使用专利，特别是AF。鉴于其对hERG的亲和力非常高，放射性衍生物可用于高通量置换研究，以检测可能与hERG结合的非心脏药物。这类药物的鉴别对于安全药理学具有相当重要的意义。该提案的具体目的是：1）完成药物对其他心脏膜电流ITo、IKs和IK 1影响的体外试验; 2）在AF动物模型中测试药物的有效性; 3）在心肌楔形制备中测试药物的安全性，该制备是目前潜在致死性室性心律失常尖端扭转型室性心动过速（TdP）的最佳预测因子;和4）表征药物同源物作为结合hERG的药物的HTS置换研究的工具。在药物通过特定目标的障碍后，ChanTest将向FDA提交355（B）（2）NDA申请，以进行II期和III期临床试验。ChanTest认为，这种药物将为许多因房颤而虚弱的人提供极大的缓解。