AC5 inhibitor for heart failure

描述(申请人提供)：心血管疾病在美国和西方国家是一个严重的健康问题。主要死因是心力衰竭(HF)。在美国，近550万患者被诊断为充血性心力衰竭，心力衰竭的主要原因是心肌缺血性疾病。因此，改善心肌梗死后心力衰竭的治疗方法是非常重要的，而开发一类新的预防心力衰竭进展的药物将具有巨大的市场机会和重大的临床进步。该项目的最终目标是开发一种通过抑制5型腺酰环化酶(AC5)来治疗心力衰竭(HF)的新药。最近，我们的研究表明，抑制AC5将成为治疗心力衰竭的一种策略。AC5基因的阻断可延缓衰老相关的心力衰竭，对慢性压力超负荷、交感神经过度刺激和心肌缺血所致心力衰竭具有保护作用，提示AC5抑制剂可能是一类新型心力衰竭药物。I期研究将提供确凿的证据，证明一种新的AC5抑制剂对小动物模型的心肌梗塞后心力衰竭有有益的影响。在我们对AC5抑制剂的初步筛选中，临床上用于不同适应症的9-D-阿拉伯呋喃诺苷(AraAde，也称为Vidarabine或Vira-A(R))在小鼠身上显示出对HF的保护作用，这表明AC5抑制剂可能用于治疗HF。在目前的应用中，我们将通过小鼠心力衰竭模型来验证新型AC5抑制剂PMC-6对心肌梗死后心力衰竭的影响。在第二阶段，我们将在一个大型动物模型中进一步研究PMC-6对心肌梗塞后心力衰竭的影响。此外，我们还将开发效力更强、特异性更好、副作用最小的第二代PMC-6类药物。我们将评估最有希望进入临床试验的第二代AC5抑制剂的药代动力学、药物代谢和安全性。

DESCRIPTION (provided by applicant): Cardiovascular disease is a critical health issue in the US and Western countries. The leading cause of death is heart failure (HF). Almost 5.5 million patients are diagnosed with congestive HF in the U.S and the major cause of HF is myocardial ischemic disease. Therefore, improvement of therapy for post myocardial infarction (post-MI) HF is extremely important, and the development of a new class of medicine which prevents progression of HF would have a large market opportunity and represent a significant clinical advance. The ultimate goal of this project is to develop a new drug for heart failure (HF) by inhibiting type 5 adenylyl cyclase (AC5). Recently our studies demonstrated that inhibition of AC5 would be a strategy for treating HF. Disruption of AC5 gene in mouse prolongs lifespan by attenuating aging-related HF, protects against HF induced by chronic pressure overload, by excessive sympathetic stimulation and by myocardial ischemia, suggesting that an AC5 inhibitor would be a new class of HF drug. The phase I study will provide definitive evidence that a novel AC5 inhibitor has beneficial effect on post-MI HF in a small animal model. In our preliminary screening for AC5 inhibitors, adenine 9-D-arabinofuranoside (AraAde, also known as Vidarabine or Vira-A(R)), which was used in the clinic for a different indication, showed protection against HF in mice, suggesting a possible clinical utility of AC5 inhibitors for treating HF. In the presen application we will validate the effect of a novel AC5 inhibitor, PMC-6, on post-MI HF by using a mouse HF model. In the Phase II, we will further investigate the effect of PMC-6 on post-MI HF in a large animal model. Additionally, we will develop second generation PMC-6-type drugs with improved potency, better specificity and minimal adverse effects. We will evaluate the pharmacokinetics, drug metabolism, and safety of the most promising second generation AC5 inhibitor to enter into clinical trials.