AC5 inhibitor for heart failure

描述（由申请人提供）：心血管疾病是美国和西方国家的一个严重健康问题。死亡的主要原因是心力衰竭（HF）。在美国，大约有550万患者被诊断患有充血性HF，HF的主要原因是心肌缺血性疾病。因此，改善心肌梗死后（MI后）HF的治疗是极其重要的，并且开发防止HF进展的新类别的药物将具有很大的市场机会并且代表显著的临床进步。 本项目的最终目标是通过抑制5型腺苷酸环化酶（AC 5）来开发治疗心力衰竭（HF）的新药。最近我们的研究表明，AC 5的抑制将是治疗HF的策略。AC 5基因的阻断可减轻衰老相关的HF，对慢性压力超负荷、过度交感神经刺激和心肌缺血引起的HF具有保护作用，提示AC 5抑制剂有望成为一类新的HF治疗药物。 I期研究将提供明确的证据，证明新型AC 5抑制剂在小动物模型中对MI后HF具有有益作用。在我们对AC 5抑制剂的初步筛选中，腺嘌呤9-D-阿拉伯呋喃糖苷（AraAde，也称为Vidarabine或Vira-A（R））在临床上用于不同的适应症，在小鼠中显示出对HF的保护作用，表明AC 5抑制剂治疗HF的可能临床用途。在本申请中，我们将通过使用小鼠HF模型来验证新型AC 5抑制剂PMC-6对MI后HF的作用。 在II期研究中，我们将在大型动物模型中进一步研究PMC-6对MI后HF的影响。此外，我们将开发第二代PMC-6型药物，其效力更高，特异性更好，副作用最小。我们将评估最有前途的第二代AC 5抑制剂的药代动力学、药物代谢和安全性，以进入临床试验。

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.