Adenylyl Cyclase Type 5 Inhibition to Treat Myocardial Infarction

项目摘要/摘要 心肌梗死(MI)治疗中最重要的进展是再灌注疗法，它 必须在诊断心肌梗死后立即应用。尽管有数以千计的药物研究 旨在缩小心肌梗死大小的疗法大多在临床试验中失败了。我们的假设是一个主要的 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给药 已执行。这大大限制了它们在临床环境中的应用。目前的建议是基于对 腺酰环化酶5(AC5)基因敲除小鼠模型，该模型对心肌缺血具有保护作用， 肥胖，糖尿病，并有增强的运动能力和寿命比野生的。我们的初步数据 证明AC5酶的药物抑制剂有一个独特的优势，那就是它们可以减少 即使在冠脉再灌流后给药，也能扩大梗塞面积。我们开发了一种新颖的，更有效的和 更具选择性的AC5抑制剂，C90，特别吸引人，因为它是一种有效的非核苷腺嘌呤 AC5抑制剂，也无毒。我们正在申请C90的专利，并选择了这种化合物用于临床 基于疗效、药理和安全性的开发。初步数据表明，C90可以减少脑梗塞 在小鼠心肌梗死模型中，再灌流后给药的大小增加了50%以上。这项提议的目标是 在小鼠、患有动脉粥样硬化的渡边兔和大型哺乳动物动物中获得原则证据 梗死面积、心功能和完整的IND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.