BMS-986235
(Synonyms: LAR-1219) 目录号 : GC60649BMS-986235(LAR-1219)是一种选择性、具有口服活性的甲酰肽受体2(FPR2)激动剂,对hFPR2和mFPR2的EC50分别为0.41nM和3.4nM。BMS-986235具有预防心力衰竭的潜力。
Cas No.:2253947-47-4
Sample solution is provided at 25 µL, 10mM.
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BMS-986235 (LAR-1219) is a selective, orally active formyl peptide receptor 2 (FPR2) agonist, with EC50s of 0.41 nM and 3.4 nM for hFPR2 and mFPR2, respectively. BMS-986235 has potential for the prevention of heart failure[1].
BMS-986235 (LAR-1219) inhibits neutrophil chemotaxis and stimulats macrophage phagocytosis, key end points to promote resolution of inflammation[1].
BMS-986235 (LAR-1219) (0.3 mg/kg; p.o.; daily for 24 days) can attenuate left ventricle and global cardiac remodeling after left anterior descending (LAD) in mice[1].BMS-986235 (1 mg/kg; p.o.) treatment shows the Cmax, T1/2, AUC0-inf, and bioavailability (BA) values of 160 nmol/L, 0.68 hours,120 nmol/L•h, and 24%, respectively[1]. Animal Model: Male C57BL/6 mice[1]
[1]. Asahina Y, et al. Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure [published online ahead of print, 2020 May 24]. J Med Chem. 2020;10.1021/acs.jmedchem.9b02101.
Cas No. | 2253947-47-4 | SDF | |
别名 | LAR-1219 | ||
Canonical SMILES | O=C(NC1=CC=CC=C1)N[C@@H]2C(NC[C@H]2C3=C(F)C=C(OC)C=C3F)=O | ||
分子式 | C18H17F2N3O3 | 分子量 | 361.34 |
溶解度 | 储存条件 | Store at -20°C | |
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1 mg | 5 mg | 10 mg | |
1 mM | 2.7675 mL | 13.8374 mL | 27.6748 mL |
5 mM | 0.5535 mL | 2.7675 mL | 5.535 mL |
10 mM | 0.2767 mL | 1.3837 mL | 2.7675 mL |
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Selective FPR2 Agonism Promotes a Proresolution Macrophage Phenotype and Improves Cardiac Structure-Function Post Myocardial Infarction
JACC Basic Transl Sci 2021 Aug 23;6(8):676-689.PMID:34466754DOI:10.1016/j.jacbts.2021.07.007.
Dysregulated inflammation following myocardial infarction (MI) leads to maladaptive healing and remodeling. The study characterized and evaluated a selective formyl peptide receptor 2 (FPR2) agonist BMS-986235 in cellular assays and in rodents undergoing MI. BMS-986235 activated G proteins and promoted β-arrestin recruitment, enhanced phagocytosis and neutrophil apoptosis, regulated chemotaxis, and stimulated interleukin-10 and monocyte chemoattractant protein-1 gene expression. Treatment with BMS-986235 improved mouse survival, reduced left ventricular area, reduced scar area, and preserved wall thickness. Treatment increased macrophage arginase-1 messenger RNA and CD206 receptor levels indicating a proresolution phenotype. In rats following MI, BMS-986235 preserved viable myocardium, attenuated left ventricular remodeling, and increased ejection fraction relative to control animals. Therefore, FPR2 agonism improves post-MI healing, limits remodeling and preserves function, and may offer an innovative therapeutic option to improve outcomes.
Molecular Mechanisms of Desensitization Underlying the Differential Effects of Formyl Peptide Receptor 2 Agonists on Cardiac Structure-Function Post Myocardial Infarction
ACS Pharmacol Transl Sci 2022 Sep 14;5(10):892-906.PMID:PMC9578139DOI:10.1021/acsptsci.2c00042.
Formyl peptide receptor 2 (FPR2) plays an integral role in the transition of macrophages from a pro-inflammatory program to one that is pro-resolving. FPR2-mediated stimulation of resolution post myocardial infarction has demonstrated efficacy in rodent models and is hypothesized to reduce progression into heart failure. FPR2 agonists that promote long-lasting receptor internalization can lead to persistent desensitization and diminished therapeutic benefits. In vitro signaling profiles and propensities for receptor desensitization of two clinically studied FPR2 agonists, namely, BMS-986235 and ACT-389949, were evaluated. In contrast to BMS-986235, pre-stimulation with ACT-389949 led to a decrease in its potency to inhibit cAMP production. Moreover, ACT-389949 displayed greater efficacy for β-arrestin recruitment, while efficacy of Gi activation was similar for both agonists. Following agonist-promoted FPR2 internalization, effective recycling to the plasma membrane was observed only with BMS-986235. Use of G protein-coupled receptor kinase (GRK) knock-out cells revealed a differential impact of GRK2 versus GRK5/6 on β-arrestin recruitment and Gi activation promoted by the two FPR2 agonists. In vivo, decreases of granulocytes in circulation were greatly diminished in mice treated with ACT-389949 but not for BMS-986235. With short-term dosing, both compounds induced a pro-resolution polarization state in cardiac monocyte/macrophages post myocardial infarction. By contrast, with long-term dosing, only BMS-986235 preserved the infarct wall thickness and increased left ventricular ejection fraction in a rat model of myocardial infarction. Altogether, the study shows that differences in the desensitization profiles induced by ACT-389949 and BMS-986235 at the molecular level may explain their distinct inflammatory/pro-resolving activities in vivo.