New drugs for treatment of atrial fibrillation

心房颤动（AF）是最常见的心律失常，其慢性形式影响了美国200多万患者。房颤与心脏和非心脏疾病有关。约10%的病例无明显病因（单发房颤）。中风是最常见的并发症，在老年人群中比对照组的风险高25%。阻断钠、钾和钙通道的药物提供了常规的治疗方法。所有这些药物都可能有毒副作用，因为它们的离子通道靶点存在于心室，而心室的阻滞可能导致致命性心律失常。我们的长期目标是开发一种令人满意的房颤药物。作为第一步，我们已经确定了一个新的靶点，该靶点仅限于人类心房，因此应该没有室性心律失常的风险。这项提议的具体目的是发现新的、选择性的药物作用于心房划定的靶点来治疗房颤。新的靶点将在细胞系中表达，用于从定向和多样性文库中获得的小化合物的高通量功能筛选。确认的线索将被充分表征，两年内应该有两到五个临床前候选药物。拟议的商业应用：心房颤动是一种非常常见的疾病，目前尚无令人满意的治疗方法。一种疗效高、毒性小的药物具有很大的治疗价值和商业价值。

Atrial fibrillation (AF) is the commonest cardiac arrhythmia and in its chronic form affects more than two million patients in the USA. AF is associated with cardiac and non-cardiac diseases. About 10% of cases have no obvious cause (lone AF). Stroke is the commonest complication with a 25% greater risk than control in older age groups. Drugs that block sodium, potassium and calcium channels provide the customary treatment. All of these drugs may have toxic side effects because their ion cannel targets are present in ventricle where block may produce lethal arrhythmias. Our long-term objective is to develop a satisfactory drug for AF. As a first step we have identified a novel target that is limited to human atrium and should therefore be free from the risk of ventricular arrhythmias. The specific aim of this proposal is to discover novel, selective drugs acting on this atrial-delimited target for the treatment of AF. The novel target will be expressed in cell lines for use in high throughput functional screens of small compounds derived from directed and diversity libraries. Confirmed leads will be fully characterized and two to five preclinical drug candidates should be available within two years. PROPOSED COMMERCIAL APPLICATIONS: Atrial fibrillation is a very common disease for which there is no satisfactory treatment. A drug that has high efficacy with little toxicity would have great therapeutic and commercial value.