Adenylyl Cyclase Type 5 Inhibition to Treat Myocardial Infarction

项目总结/摘要 心肌梗死（MI）治疗中最重要的进展是再灌注治疗， 必须在MI诊断后立即应用。尽管有成千上万的关于药物的研究 设计用于减小MI大小的治疗，大多数在临床试验中失败。我们的假设是， 这些药物失败的原因是它们必须在治疗性心导管插入术之前施用。 执行。这大大限制了它们在临床环境中的效用。目前的建议是根据下列研究提出的： 腺苷酸环化酶5型（AC 5）敲除小鼠模型，其被保护免于心肌缺血， 肥胖症、糖尿病，运动能力增强，寿命长于野生型。我们的初步数据 证明AC 5酶的药理学抑制剂具有独特的优势，因为它们减少了 即使在冠状动脉再灌注后给药，我们开发了一种新的，更有效的， 更有选择性的AC 5抑制剂，C90，这是特别有吸引力的，因为它是一种有效的非核苷腺嘌呤 AC 5抑制剂也是无毒的。我们有一个关于C90的专利申请，并选择了这种化合物用于临床 基于疗效、药理学和安全性的开发。初步数据表明，C90可以减少梗死 在小鼠MI模型中，当在再灌注后施用时，其大小超过50%。这项提案的目的是 在小鼠、患有动脉粥样硬化的Watanabe兔和大型哺乳动物中获得原理验证 用于梗死面积、心脏功能和完整IND使能药理学、ADME和毒理学研究的模型。

PROJECT SUMMARY/ABSTRACT The most significant advance in the treatment of Myocardial Infarction (MI) has been reperfusion therapy, which must be applied immediately after the MI diagnosis has been made. Despite the thousands of studies on drug therapies designed to reduce the size of the MI, most have failed in clinical trials. Our hypothesis is that a major reason why these drugs failed is that they must be administered before therapeutic cardiac catheterization is performed. This significantly limits their utility in the clinical setting. The current proposal is based on studies in the Adenylyl Cyclase type 5 (AC5) knock out mouse model, which is protected against myocardial ischemia, obesity, diabetes and has enhanced exercise capacity and lives longer than wild type. Our preliminary data demonstrate that pharmacological inhibitors of the AC5 enzyme have a unique advantage in that they reduce infarct size even when administered after coronary reperfusion. We have developed a novel, more potent and more selective AC5 inhibitor, C90, which is particularly attractive because it is a potent non-nucleoside adenine AC5 inhibitor and also is not toxic. We have a patent pending on C90 and selected this compound for clinical development based on efficacy, pharmacology and safety. Preliminary data indicate that C90 can reduce infarct size when administered after reperfusion by more than 50% in a mouse MI model. The goal of this proposal is to obtain proof-of-principle in mice, in Watanabe rabbits with atherosclerosis and in a large mammalian animal model for infarct size, cardiac function and complete IND-enabling pharmacology, ADME and toxicology studies.