Background:New heart failure therapies that safely augment cardiac contractility and output are needed. Previous apelin peptide studies have highlighted the potential for APJ (apelin receptor) agonism to enhance cardiac function in heart failure. However, apelin’s short half-life limits its therapeutic utility. Here, we describe the preclinical characterization of a novel, orally bioavailable APJ agonist, BMS-986224.Methods:BMS-986224 pharmacology was compared with (Pyr¹) apelin-13 using radio ligand binding and signaling pathway assays downstream of APJ (cAMP, phosphorylated ERK [extracellular signal-regulated kinase], bioluminescence resonance energy transfer–based G-protein assays, β-arrestin recruitment, and receptor internalization). Acute effects on cardiac function were studied in anesthetized instrumented rats. Chronic effects of BMS-986224 were assessed echocardiographically in the RHR (renal hypertensive rat) model of cardiac hypertrophy and decreased cardiac output.Results:BMS-986224 was a potent (Kd=0.3 nmol/L) and selective APJ agonist, exhibiting similar receptor binding and signaling profile to (Pyr¹) apelin-13. G-protein signaling assays in human embryonic kidney 293 cells and human cardiomyocytes confirmed this and demonstrated a lack of signaling bias relative to (Pyr¹) apelin-13. In anesthetized instrumented rats, short-term BMS-986224 infusion increased cardiac output (10%–15%) without affecting heart rate, which was similar to (Pyr¹) apelin-13 but differentiated from dobutamine. Subcutaneous and oral BMS-986224 administration in the RHR model increased stroke volume and cardiac output to levels seen in healthy animals but without preventing cardiac hypertrophy and fibrosis, effects differentiated from enalapril.Conclusions:We identify a novel, potent, and orally bioavailable nonpeptidic APJ agonist that closely recapitulates the signaling properties of (Pyr¹) apelin-13. We show that oral APJ agonist administration induces a sustained increase in cardiac output in the cardiac disease setting and exhibits a differentiated profile from the renin-angiotensin system inhibitor enalapril, supporting further clinical evaluation of BMS-986224 in heart failure.

中文翻译：

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小分子APJ（Apelin受体）激动剂BMS-986224的体外和体内评估，可作为治疗心力衰竭的一种方法

背景：需要能够安全增加心脏收缩力和输出功率的新的心力衰竭治疗方法。先前的apelin肽研究强调了APJ（apelin受体）激动剂增强心力衰竭心脏功能的潜力。但是，apelin的半衰期短限制了其治疗用途。在这里，我们描述了一种新型的，可口服生物利用的APJ激动剂BMS-986224的临床前表征。方法：将BMS-986224药理学与（Pyr ¹）apelin-13使用APJ下游的放射性配体结合和信号通路测定（cAMP，磷酸化ERK（细胞外信号调节激酶），基于生物发光共振能量转移的G蛋白测定，β-arrestin募集和受体内化）。在麻醉的麻醉大鼠中研究了其对心脏功能的急性影响。BMS-986224在RHR（肾性高血压大鼠）心脏肥大和心输出量减少的模型中以超声心动图评估其慢性作用。结果：BMS-986224是一种有效的（Kd = 0.3 nmol / L）和选择性APJ激动剂，表现出相似的受体与（Pyr ^1的结合和信号传导图）apelin-13。人胚胎肾293细胞和人心肌细胞中的G蛋白信号转导测定证实了这一点，并证明相对于（Pyr ¹）apelin-13缺乏信号转导偏向。在麻醉的器械大鼠中，短期BMS-986224输注可增加心输出量（10％–15％），而不会影响心率，这与（Pyr ¹）apelin-13类似，但与多巴酚丁胺有所区别。在RHR模型中皮下和口服BMS-986224可使中风量和心输出量增加至健康动物所见的水平，但不能预防心脏肥大和纤维化，其作用与依那普利不同。结论：我们确定了一种新颖，有效且可口服生物利用的非肽类APJ激动剂，它密切概括了（Pyr ¹的信号传导特性）apelin-13。我们显示口服APJ激动剂给药可在心脏疾病环境中诱导持续增加的心输出量，并表现出与肾素-血管紧张素系统抑制剂依那普利不同的特性，支持BMS-986224在心力衰竭中的进一步临床评估。