BMS-986224
目录号 : GC65508BMS-986224 是一种有效选择性和具有口服活性的 APJ 受体激动剂 (Kd = 0.3 nM),表现出与 (Pyr1) apelin-13 相似的受体结合和信号传导谱。BMS-986224 具有研究心力衰竭的潜力。
Cas No.:2055200-88-7
Sample solution is provided at 25 µL, 10mM.
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BMS-986224 is a potent, selective and orally active APJ receptor agonist (Kd = 0.3 nM). BMS-986224 exhibits similar receptor binding and signaling profile to (Pyr1) apelin-13. BMS-986224 has the potential for the research of heart failure[1].
BMS-986224 fully inhibits forskolin-mediated cAMP production, with an EC50 for human APJ of 0.02 nM. BMS-986224 (0-100 nM) fully stimulates β-arrestin recruitment, ERK phosphorylation, and APJ internalization in Chinese hamster ovary-K1 or HEK293 ZF cells[1].BMS-986224 is a potent and selective APJ receptor agonist that exhibits a similar signaling profile to (Pyr1) apelin-13[1].
BMS-986224 (0.192 mg/kg or 3 mg/kg; SC infusion; daily;) 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[1].
[1]. Gargalovic P, et al. In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure. Circ Heart Fail. 2021;14(3):e007351.
Cas No. | 2055200-88-7 | SDF | Download SDF |
分子式 | C24H23ClN4O6 | 分子量 | 498.92 |
溶解度 | DMSO : 20.83 mg/mL (41.75 mM; ultrasonic and warming and heat to 60°C) | 储存条件 | Store at -20°C |
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In Vitro and In Vivo Evaluation of a Small-Molecule APJ (Apelin Receptor) Agonist, BMS-986224, as a Potential Treatment for Heart Failure
Circ Heart Fail 2021 Mar;14(3):e007351.PMID:33663236DOI:10.1161/CIRCHEARTFAILURE.120.007351.
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.
Identification of 6-Hydroxypyrimidin-4(1 H)-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists
ACS Med Chem Lett 2021 Oct 22;12(11):1766-1772.PMID:34795866DOI:10.1021/acsmedchemlett.1c00385.
The apelin receptor (APJ) is a significant regulator of cardiovascular function and is involved in heart failure and other cardiovascular diseases. (Pyr1)apelin-13 is one of the endogenous agonists of the APJ receptor. Administration of (Pyr1)apelin-13 increases cardiac output in preclinical models and humans. Recently we disclosed clinical lead BMS-986224 (1), a C3 oxadiazole pyridinone APJ receptor agonist with robust pharmacodynamic effects similar to (Pyr1)apelin-13 in an acute rat pressure-volume loop model. Herein we describe the structure-activity relationship of the carboxamides as oxadiazole bioisosteres at C3 of the pyridinone core and C5 of the respective pyrimidinone core. This study led to the identification of structurally differentiated 6-hydroxypyrimidin-4(1H)-one-3-carboxamide 14a with pharmacodynamic effects comparable to those of compound 1.