Activation of the Secretin Receptor as a Strategy for the Treatment of Heart Failure

激活促胰液素受体作为治疗心力衰竭的策略

• 批准号: 10532360
• 负责人: Robert Ardecky
• 金额: $ 60.52万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-05 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532360
• 关键词: Acute; Adipocytes; Affect; Agonist; Angiotensin Receptor; Animal Model; Biological Assay; Biological Availability; Blood; Blood Vessels; Cardiac; Cardiac Output; Cardiovascular Diseases; Cardiovascular system; Cell model; Chemicals; Chemistry; Circulation; Clinical; Clinical Trials; Communities; Congestive Heart Failure; Contracts; Data; Desire for food; Development; Diabetes Mellitus; Drug Combinations; Drug Kinetics; EFRAC; Epidemic; Excretory function; Exhibits; FDA approved; Funding; Future; G-Protein-Coupled Receptors; Glucose; Goals; Grant; Half-Life; Heart; Heart failure; Hospitalization; In Vitro; Incidence; Lead; Life; Medicine; Metabolism; Modeling; Modification; Morbidity - disease rate; Myocardial; Myocardial Ischemia; Myosin ATPase; Natriuretic Peptides; Neprilysin; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oral; Outpatients; Oxygen Consumption; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Peptides; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Population; Prognosis; Property; Protease Inhibitor; Rattus; Receptor Signaling; Reporting; Reproducibility; Rodent; Satiation; Secretin; Series; Signal Pathway; Specificity; System; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Thiadiazoles; Validation; Vascular resistance; Work; absorption; analog; coronary perfusion; design; drug candidate; enzyme substrate; glucose metabolism; high throughput screening; improved; in vitro Model; in vivo; islet; lead series; meter; mortality; novel; parenteral administration; peptide hormone; pharmacologic; positive allosteric modulator; readmission rates; receptor; scaffold; secretin receptor; side effect; small molecule; standard of care; targeted treatment; therapeutic effectiveness; treatment strategy

PROJECT SUMMARY/ABSTRACT Heart failure is a major cause of morbidity and mortality in the population, with rising incidence of cardiovascular disease contributed to by epidemic increases in obesity and associated type 2 diabetes mellitus. Although existing drugs are effective in acutely correcting decompensated heart failure, this continues to be associated with unacceptable rates of rehospitalization and mortality. A drug combination adding neprilysin inhibition to the previous standard-of-care for heart failure, angiotensin receptor blockade, was recently approved by the FDA based on its ability to extend the life of patients with reduced cardiac output. However, the broad action of the peptidase inhibitor in this combination could theoretically be improved, thereby reducing possible side effects and increasing therapeutic effectiveness. The specific enzyme substrate responsible for the beneficial effects of this drug is not yet clear. While it has been assumed to be natriuretic peptides, other peptides are also cleaved by neprolysin, many of which have potential offsetting and/or side effects. Another prominent potentially beneficial substrate of this protease is secretin, a peptide hormone with useful effects on cardiac contractility and ejection fraction, coronary perfusion, peripheral vascular resistance, post-cibal satiety, and glucose-sensitive incretin action. Prior to work supported by this grant in its previous funding cycle, there were no small molecules known to mimic or enhance secretin activity at its receptor. In that work, we screened nearly 400,000 compounds and identified several structural classes of compounds that demonstrate robust and reproducible activation of secretin receptor signaling in vitro in model cell systems. As a continuation of those encouraging data, we now propose to utilize medicinal chemical approaches to optimize the scaffolds identified in the previous work. These include compounds with the ability to act as positive allosteric modulators of secretin action, as well as those having intrinsic agonist activity. We will utilize cycles of systematic chemical modification and rational enhancement with in vitro pharmacologic characterization to improve their pharmacological and ADME/T properties (Aims 1 and 2). The best candidates in each structural series will be studied using in vivo animal models to evaluate their oral bioavailability and efficacy, as well as an in vivo rat model of ischemic heart failure (Aim 3). Our approach will validate this receptor as an attractive target for therapeutic intervention in heart failure and provide first-in-class small molecule compounds that we hope to take into clinical trials in the future.

项目总结/摘要 心力衰竭是人群发病率和死亡率的主要原因， 肥胖和相关2型糖尿病流行性增加导致心血管疾病 糖尿病。尽管现有的药物在急性纠正失代偿性心力衰竭方面是有效的， 与不可接受的再住院率和死亡率相关。一种药物组合物， 脑啡肽酶抑制剂与之前治疗心力衰竭的标准药物血管紧张素受体阻滞剂相比， 最近被FDA批准，基于其延长心输出量减少患者生命的能力。 然而，在该组合中肽酶抑制剂的广泛作用理论上可以得到改善， 从而减少可能的副作用并提高治疗效果。特异性酶底物 这种药物的有益效果的原因尚不清楚。虽然它被认为是利钠的 除了肽外，其他肽也被脑蛋白溶酶裂解，其中许多肽具有潜在的抵消和/或侧链效应。 方面的影响.这种蛋白酶的另一个突出的潜在有益底物是分泌素，一种肽激素， 对心肌收缩力和射血分数，冠状动脉灌注，外周血管阻力， 食后饱腹感和葡萄糖敏感性肠促胰岛素作用。在此之前，这项赠款支持的工作在其以前的 在资金周期中，没有已知的小分子模拟或增强促胰液素在其受体的活性。在 在这项工作中，我们筛选了近40万种化合物，并确定了几种结构类型的化合物， 在体外模型细胞系统中证实了促胰液素受体信号传导的稳健和可再现的活化。作为 继续这些令人鼓舞的数据，我们现在建议利用药用化学方法， 优化在以前的工作中确定的支架。这些化合物包括能够作为 促胰液素作用的正变构调节剂，以及具有内在激动剂活性的那些。我们将利用 系统的化学修饰和合理的体外药理学增强循环 本发明的目的是通过表征来改善它们的药理学和ADME/T性质（目的1和2）。最佳候选人 将使用体内动物模型研究每个结构系列，以评估其口服生物利用度， 疗效，以及缺血性心力衰竭的体内大鼠模型（目的3）。我们的方法将验证这一点 受体作为心力衰竭治疗干预的有吸引力的靶点，并提供一流的小 我们希望在未来将其用于临床试验。