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

项目摘要/摘要 心力衰竭是人群中发病率和死亡率的主要原因， 肥胖和相关的2型糖尿病的流行增加导致心血管疾病 糖尿病。尽管现有的药物在纠正失代偿性心力衰竭方面是有效的，但这种情况仍在继续。 与不可接受的再住院率和死亡率有关。一种药物组合添加 奈普利辛抑制之前治疗心力衰竭的标准药物--血管紧张素受体阻滞剂 FDA最近批准了它，因为它有能力延长心输出量减少患者的生命。 然而，从理论上讲，肽酶抑制剂在这种组合中的广泛作用可以得到改善， 从而减少可能的副作用，提高治疗效果。特定的酶底物 目前还不清楚这种药物的有益效果。虽然它被认为是利钠药 多肽，其他多肽也被neprolysin切割，其中许多具有潜在的抵消和/或侧面 效果。这种蛋白酶的另一个重要的潜在有益底物是分泌素，它是一种多肽激素，具有 对心脏收缩能力和射血分数、冠脉血流灌注、外周血管阻力、 节食后的饱腹感和对葡萄糖敏感的胰岛素作用。在这笔赠款支持的工作之前， 在资金周期中，没有已知的小分子模仿或增强其受体上的分泌素活性。在……里面 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别的化合物 在体外模型细胞系统中展示促胰液素受体信号的强健和可重复性的激活。AS 作为这些令人鼓舞的数据的延续，我们现在建议利用药物化学方法来 优化前面工作中确定的脚手架。这些化合物包括具有以下作用的化合物 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 体外药理作用的系统化学修饰和合理强化的循环 改善其药理和ADME/T特性的特性(目标1和2)。最好的候选人 将使用体内动物模型对每个结构系列进行研究，以评估其口服生物利用度和 疗效，以及在体大鼠缺血性心力衰竭模型(目标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，并提供一流的小分子 我们希望在未来进行临床试验的分子化合物。

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.