AC5 inhibitor for heart failure

AC5抑制剂治疗心力衰竭

• 批准号: 8253510
• 负责人: Patricio Abarzua
• 金额: $ 20.57万
• 依托单位: VASADE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-17 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253510
• 关键词: Adenine; Adverse effects; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Animals; Apoptosis; Apoptotic; Arasena-A; Area; Attenuated; Blood - brain barrier anatomy; Canis familiaris; Carboxylic Acids; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cause of Death; Chronic; Cicatrix; Clinic; Clinical; Clinical Trials; Congestive Heart Failure; Country; Cyclopentane; Data; Data Analyses; Development; Diabetes Mellitus; Diagnosis; Disease; Drug Kinetics; EFRAC; Exercise; Fibrosis; Figs - dietary; Funding; Future; Generations; Genes; Goals; Grant; Health; Heart failure; In Vitro; Inhibitory Concentration 50; Investigation; Investigational Drugs; Legal patent; Licensing; Longevity; Marketing; Medicine; Metabolic Diseases; Modeling; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Obesity; Outcome; Patients; Permeability; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase Transition; Preparation; Rodent; Safety; Screening procedure; Solubility; Specificity; Survival Rate; Testing; Therapeutic Uses; Time; Toxicology; Vidarabine; adenylyl cyclase type V; age related; analog; base; comparative efficacy; drug metabolism; effective therapy; improved; inhibitor/antagonist; novel; novel therapeutics; phase 1 study; pressure; prevent; research study

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. PUBLIC HEALTH RELEVANCE: Almost 5.5 million patients are diagnosed with congestive HF 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 aiming at generating a new class of medicine preventing progression of HF, which should have a large market opportunity and significant clinical importance.

描述（由申请人提供）：心血管疾病是美国和西方国家的一个重要健康问题。死亡的主要原因是心力衰竭（HF）。在美国，近 550 万患者被诊断患有充血性心力衰竭，心力衰竭的主要原因是心肌缺血性疾病。因此，改善心肌梗塞后（MI后）心力衰竭的治疗极为重要，开发一类预防心力衰竭进展的新药物将拥有巨大的市场机会，并代表着重大的临床进步。 该项目的最终目标是通过抑制5型腺苷酸环化酶（AC5）来开发一种治疗心力衰竭（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。小鼠 AC5 基因的破坏可通过减弱与衰老相关的心力衰竭来延长寿命，并防止慢性压力超负荷、过度交感神经刺激和心肌缺血引起的心力衰竭，这表明 AC5 抑制剂将成为一类新型心力衰竭药物。 I 期研究将提供明确的证据，证明新型 AC5 抑制剂对小动物模型中的 MI 后心力衰竭具有有益作用。在我们对 AC5 抑制剂的初步筛选中，腺嘌呤 9-D-阿拉伯呋喃糖苷（AraAde，也称为阿糖腺苷或 Vira-A(R)）在临床中用于不同的适应症，显示出对小鼠心力衰竭的保护作用，这表明 AC5 抑制剂在治疗心力衰竭方面可能具有临床用途。在本申请中，我们将通过使用小鼠心力衰竭模型来验证新型 AC5 抑制剂 PMC-6 对 MI 后心力衰竭的效果。 在第二阶段，我们将在大型动物模型中进一步研究PMC-6对MI后心力衰竭的影响。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。 公共卫生相关性：在美国，近 550 万患者被诊断患有充血性心力衰竭，心力衰竭的主要原因是心肌缺血性疾病；然而，尚未建立有效的疗法来治疗充血性心力衰竭。目前的研究旨在开发一种预防心力衰竭进展的新型药物，该药物应该具有巨大的市场机会和显着的临床重要性。