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)是主要的死亡原因，而心力衰竭的主要原因是心肌缺血性疾病。因此，改善心肌梗死后的治疗是非常重要的，而开发一种新型的预防心力衰竭进展的药物将有很大的市场机会，代表着临床上的重大进步。此外，这些患者大多血脂升高，许多人糖代谢受损，要么是糖尿病患者，要么是糖尿病前期患者。因此，一种能对糖尿病控制起到良好作用的HF药物将在HF市场上占有独特的一席之地。这项赠款提案的目的是证明一类新的HF药物的有效性，其机制是抑制5型腺苷环化酶(ACS)，以改善慢性ML后重塑的不良反应，同时改善糖代谢紊乱。这一建议是基于我们之前在ACS基因突变的小鼠模型，即ACS基因敲除小鼠(ACSKO)中所做的工作，并基于一种特定的药理ACS抑制剂的利用。ACSKO小鼠的寿命更长，并可免受衰老所致的心肌病的影响。它们还可以防止慢性压力超负荷或过度交感神经刺激引起的心力衰竭。ACSKO小鼠模型的另一个独特特征是它能够增加冠脉储备，这在预防心力衰竭的发展方面应该特别有用。对这项提议来说，重要的是这些小鼠比野生型吃得更多，但体重更轻，这表明它们具有良好的代谢特征，这一点得到了我们使用特定药物ACS抑制剂的初步数据的证实。在我们对ACS抑制剂的初步筛选中，9-D-阿拉伯呋喃诺苷(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，药理上的AC5抑制剂可以预防慢性心力衰竭，也可以预防高脂饮食引起的小鼠高血糖的发展，这表明抑制ACS除了在保护心力衰竭方面有有益的作用外，还可以改善糖代谢。因此，在这项临床前研究中，我们将研究AraAde对伴有或不伴有糖代谢受损的心肌梗塞后心力衰竭的影响。此外，我们还将在最佳的心力衰竭临床前模型中检验这种药物的疗效，心梗后的慢性仪器化、清醒的猴子。相关性(参见说明)：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疾病。然而，目前还没有建立有效的治疗充血性心力衰竭的方法。目前的研究旨在开发一种新的药物，以防止心力衰竭的进展。由于这种情况的患者数量很大，这可能会对公众健康产生重大影响。

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.