2021年3月5日 · In this article, we report characterization of a novel, orally bioavailable APJ nonpeptide agonist molecule and describe its preclinical characterization in vitro and in vivo. 10,11 We demonstrate that BMS-986224 is a potent, selective APJ agonist that closely mimics the (Pyr 1) apelin-13 signaling profile.

2021年4月22日 · The development and implementation of two process syntheses to provide BMS-986224, an agonist of the APJ receptor, are reported. The first-generation synthesis of BMS-986224 relied on a key enamine cyclization to construct the pyridone core; however, the overall efficiency of this route was limited by the linear synthesis of the hindered biaryl ...

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 …

BMS-986224 (0-100 nM) fully stimulates β-arrestin recruitment, ERK phosphorylation, and APJ internalization in Chinese hamster ovary-K1 or HEK293 ZF cells. BMS-986224 is a potent and selective APJ receptor agonist that exhibits a similar signaling profile to (Pyr1) apelin-13 [1] .

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.

2022年7月15日 · Orally bioavailable compound 47 with favorable agonist potency (Ca 2+ EC 50 = 24 nM, cAMPi EC 50 = 6.5 nM) and pharmacokinetic properties (clearance ∼20 mL/min/kg in rats) was identified. This compound has vastly reduced brain penetration and is devoid of significant off-target liability.

Apelin-13 is an endogenous peptidic agonist of the apelin receptor (APJ) receptor with the potential for improving cardiac function in heart failure patients. However, the low plasma stability of apelin-13 necessitates continuous intravenous infusion for therapeutic use.

2021年3月5日 · 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...

2016年8月15日 · The APJ receptor is an attractive therapeutic target because of its involvement in cardiovascular diseases and potentially other disorders including liver fibrosis, obesity, diabetes, and neuroprotection. To date, pharmacological characterization of the APJ receptor has been limited due to the lack of small molecule functional agonists or ...