AC5 Inhibitor Treatment for Heart Failure

描述（由申请人提供）： 在美国，充血性心力衰竭（HF）是导致死亡的主要原因，而HF的主要原因是心肌缺血性疾病。因此，改善心肌梗塞（MI）后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，代表显著的临床进步。此外，这些患者中的大多数具有升高的血脂，并且许多具有受损的葡萄糖代谢，并且是糖尿病或糖尿病前期。因此，能够对糖尿病控制发挥有利作用的HF药物将在HF市场中具有独特的利基。该资助提案的目标是证明一类新型HF药物的功效，其具有抑制5型腺苷酸环化酶（ACS）的机制，以改善慢性MI后重塑的不良作用，并同时改善葡萄糖代谢紊乱。该提议基于我们先前在ACS基因破坏的小鼠模型中的工作，即，ACS敲除小鼠（ACS KO），并基于特定药理学ACS抑制剂的利用。ACS KO小鼠的寿命延长，并免受衰老引起的心肌病的影响。它们还可以防止由慢性压力超负荷或过度交感神经刺激诱导的HF的发展。ACS KO小鼠模型的另一个独特特征是其增加冠状动脉储备的能力，这在预防HF的发展中特别有用。重要的是，对于这个提议，这些小鼠比野生型吃得更多，但体重更轻，这表明了有利的代谢特征，我们使用特定药理学ACS抑制剂的初步数据证实了这一点。在我们对ACS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，即，治疗病毒感染，显示出对ACS的有效和选择性抑制。此外，我们的初步数据表明，药理学AC 5抑制剂在慢性MI后保护免受HF，并且还保护免受小鼠中由高脂肪饮食诱导的高血糖症的发展，这表明ACS的抑制除了在保护免受HF方面的有益作用之外还改善葡萄糖代谢。因此，在这项临床前研究中，我们将检查阿糖胞苷对伴有或不伴有糖代谢受损的MI后HF的影响。此外，我们将在HF的最佳临床前模型中检查该药物的疗效，该模型为MI后的慢性仪器清醒猴。 相关性（参见说明）：在美国，近550万患者被诊断患有充血性心力衰竭，HF的主要原因是心肌缺血性疾病。然而，还没有建立有效的治疗充血性HF的疗法。目前的研究旨在产生一类新的药物，将防止HF的进展。由于患有这种疾病的患者人数众多，这可能会对公共卫生产生重大影响。

DESCRIPTION (provided by applicant): Congestive heart failure (HF) in the U.S is the leading cause of death, and the major cause of HF is myocardial ischemic disease. Therefore, improvement of therapy post myocardial infarction (Ml) is extremely important, and the development of a new class of medicine that prevents the progression of HF would have a large market opportunity, representing a significant clinical advance. Additionally, most of these patients have elevated blood lipids and many have impaired glucose metabolism and are either diabetic or pre-diabetic. Therefore, a HF drug which can exert a favorable effect on diabetes control will have a unique niche in the HF market. The goal of this grant proposal is to demonstrate the efficacy of a new class of HF drugs, with a mechanism of inhibition of type 5 adenylyl cyclase (ACS), to improve the adverse effects of remodeling following chronic Ml and to simultaneously improve disorders of glucose metabolism,. This proposal is based on our prior work in a mouse model with disruption of the ACS gene, i.e., ACS knockout mice (ACS KO), and based on the utilization of a specific pharmacological ACS inhibitor. ACS KO mice have prolonged lifespan and are protected from the cardiomyopathy of aging. They are also protected against the development of HF induced by either chronic pressure overload, or by excessive sympathetic stimulation. Another unique feature of the ACS KO mouse model is its ability to increase coronary reserve, which should be particularly useful in preventing the development of HF. Importantly for this proposal these mice eat more than wild type, but weigh less, which points to a favorable metabolic profile, confirmed by our preliminary data using a specific pharmacological ACS inhibitor. In our preliminary screening for ACS inhibitors, adenine 9-?-D-arabinofuranoside (AraAde, also known as Vidarabine or Vira-A(r)), which was used in the clinic for a different indication, i.e., treating viral infections, showed potent and selective inhibition of ACS. Furthermore, our preliminary data demonstrate that the pharmacological AC 5 inhibitor protects against HF following chronic Ml and also protects against development of hyperglycemia induced by a high-fat diet in mice, suggesting that inhibition of ACS improves glucose metabolism in addition to its salutary effects in protecting against HF. Accordingly, in this preclinical study, we will examine the effects of AraAde on post-MI HF with or without impaired glucose metabolism. In addition we will examine the efficacy of this drug in the best pre-clinical model for HF, the chronically instrumented, conscious monkey post-MI. RELEVANCE (See instructions): Almost 5.5 million patients are diagnosed with congestive heart failure in the U.S and the major cause of HF is myocardial ischemic disease. However, no effective therapy has been established to treat congestive HF. The current investigation is aimed at generating a new class of medicine that will prevent progression of HF. Due to the large number of patients with this condition, this may have a significant impact on public health.