AC5 inhibitor for heart failure

AC5抑制剂治疗心力衰竭

基本信息

批准号：
8695476
负责人：
Dorothy Eileen Vatner
金额：
$ 85.66万
依托单位：
VASADE BIOSCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-17 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8695476
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 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 screening

项目摘要

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.

描述（由申请人提供）：心血管疾病是美国和西方国家的关键健康问题。死亡的主要原因是心力衰竭（HF）。在美国，将近550万患者被诊断出患有充血性HF，而HF的主要原因是心肌缺血性疾病。因此，改善心肌后梗塞（MI后）HF的治疗非常重要，并且开发了一种新的医学类，以防止HF的进展会有很大的市场机会，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）来开发一种新药物（HF）。最近，我们的研究表明，抑制AC5将是治疗HF的策略。小鼠中AC5基因的破坏通过衰减与衰老相关的HF延长寿命，可预防慢性压力超负荷引起的HF，过多的交感神经刺激和心肌缺血，这表明AC5抑制剂将是一种新的HF药物。第一阶段的研究将提供明确的证据，表明新型的AC5抑制剂对小动物模型中MI HF具有有益作用。在我们对AC5抑制剂的初步筛查中，腺嘌呤9-D-阿拉滨呋喃糖苷（ARAADE，也称为Vidarabine或Vira-A（R））在诊所中用于不同指示的诊所中，在鼠标中显示了对HF的保护，在鼠标中表现出对HF的保护，暗示了AC5抑制剂可用于治疗HF的临床实用性。在Presen应用中，我们将通过使用小鼠HF模型来验证新型AC5抑制剂PMC-6对MI HF的影响。在第二阶段，我们将进一步研究PMC-6对大型动物模型中MI后HF的影响。此外，我们将开发第二代PMC-6型药物，具有提高效力，更好的特异性和最小的不良反应。我们将评估最有前途的第二代AC5抑制剂的药代动力学，药物代谢以及进入临床试验的安全性。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A novel adenylyl cyclase type 5 inhibitor that reduces myocardial infarct size even when administered after coronary artery reperfusion.

一种新型腺苷酸环化酶 5 型抑制剂，即使在冠状动脉再灌注后给药，也能减少心肌梗塞面积。

DOI：
10.1016/j.yjmcc.2018.05.014
发表时间：
2018
期刊：
Journal of molecular and cellular cardiology
影响因子：
5
作者：
Zhang,Jie;Levy,Daniel;Oydanich,Marko;Bravo,ClaudioA;Yoon,Seonghun;Vatner,DorothyE;Vatner,StephenF
通讯作者：
Vatner,StephenF