Adomeglivant (LY2409021)
(Synonyms: 阿度格列凡; LY2409021) 目录号 : GC31322
Adomeglivant (LY2409021)是一种强效、选择性、口服给药的竞争性小分子胰高血糖素受体拮抗剂，Ki值为6.66nM。
Cas No.:1488363-78-5
Sample solution is provided at 25 µL, 10mM.
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Adomeglivant (LY2409021) is a potent, selective, orally administered, competitive, small-molecule antagonist of the glucagon receptor, with a Ki value of 6.66nM [1]. Adomeglivant blocks the glucagon signalling to cause a reduction of fasting and postprandial glucose[2]. Adomeglivant has been widely used to improve lipid levels and insulin resistance in mouse models of diabetes[3].
In vitro, Adomeglivant pretreatment for 20min blocked the effect of enhancing cAMP levels of glucagon (1nM) in HEK293-GLP-1R cells transfected with H188 plasmid, with an IC50 value of 1.2µM[4]. Treatment with 50μM Adomeglivant for 24h significantly inhibited the glucagon pathway in Japanese flounder liver cells, reduced glucose production in the cells, and resulted in a significant increase in the concentrations of lactate and pyruvate [5]. Adomeglivant treatment at 2μM for 24h significantly reduced ceramide levels and inhibited glucagon-stimulated lipotoxic apoptosis in H9c2 cells overexpressing glucagon receptor, as indicated by reduced cleaved caspase-3 levels[6].
In vivo, a single dose of Adomeglivant (5mg/kg) administered intraperitoneally for 30min inhibited the increase in blood glucose induced by clozapine N-oxide (3mg/kg; i.p.) [7]. Intraperitoneal administration of Adomeglivant at a dose of 2mg/kg/week for two consecutive weeks significantly reduced AMPK pathway activation and promoted p21Cip1 and p16Ink4a expression in islets of treadmill-trained mice[8].
References:
[1] Kelly R P, Garhyan P, Raddad E, et al. Short‐term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes[J]. Diabetes, Obesity and Metabolism, 2015, 17(4): 414-422.
[2] Kelly R P, Garhyan P, Raddad E, et al. Short‐term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes[J]. Diabetes, Obesity and Metabolism, 2015, 17(4): 414-422.
[3] Honzawa N, Fujimoto K, Kitamura T. Cell autonomous dysfunction and insulin resistance in pancreatic α cells[J]. International Journal of Molecular Sciences, 2019, 20(15): 3699.
[4] Chepurny O G, Matsoukas M T, Liapakis G, et al. Nonconventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP[J]. Journal of Biological Chemistry, 2019, 294(10): 3514-3531.
[5] Yang M, Pan M, Huang D, et al. Glucagon promotes gluconeogenesis through the GCGR/PKA/CREB/PGC-1α pathway in hepatocytes of the Japanese flounder Paralichthys olivaceus[J]. Cells, 2023, 12(7): 1098.
[6] Li L, Huang K, Wang D, et al. Chlorogenic acid and ferulic acid in SMYAD alleviate diabetic cardiomyopathy by inhibiting cardiac lipotoxicity via GCGR/PPARα and GCGR/AMPK pathways[J]. Phytomedicine, 2025: 156906.
[7] Kim A, Knudsen J G, Madara J C, et al. Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes[J]. Elife, 2021, 10: e72919.
[8] Carapeto P, Iwasaki K, Hela F, et al. Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence[J]. Nature metabolism, 2024, 6(10): 1976-1990.
Adomeglivant (LY2409021)是一种强效、选择性、口服给药的竞争性小分子胰高血糖素受体拮抗剂，Ki值为6.66nM[1]。Adomeglivant通过阻断胰高血糖素信号传导，有效降低空腹及餐后血糖水平[2]。Adomeglivant已广泛应用于糖尿病小鼠模型中改善血脂水平和胰岛素抵抗[3]。
在体外，使用Adomeglivant预处理转染H188质粒的HEK293-GLP-1R细胞20分钟，可阻断1nM的胰高血糖素提高cAMP水平的作用，IC50值为1.2µM[4]。用50μM的Adomeglivant处理Japanese flounder肝细胞24小时，能显著抑制胰高血糖素通路，减少细胞葡萄糖生成，并显著提高乳酸和丙酮酸浓度[5]。以2μM的Adomeglivant处理过表达胰高血糖素受体的H9c2细胞24小时，可降低神经酰胺水平，并通过减少裂解型caspase-3抑制胰高血糖素刺激的脂毒性凋亡[6]。
在体内，单次腹腔注射5mg/kg剂量的Adomeglivant 30分钟，能抑制clozapine N-oxide(3mg/kg; i.p.)诱导的小鼠血糖升高[7]。连续两周每周腹腔注射2mg/kg/week剂量的Adomeglivant，可降低跑步机训练小鼠胰岛中AMPK通路的活化，并促进p21Cip1和p16Ink4a的表达[8]。
| Cell experiment [1]: | |
Cell lines | H9c2 cells |
Preparation Method | H9c2 cells were cultured in DMEM medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin. The culture conditions were 37℃ and 5% CO2 in a humidified incubator. H9c2 cells were transfected with an adenovirus vector carrying the glucagon receptor gene (Ad GCGR) at a 10-fold concentration for 24 hours. Subsequently, the cells were stimulated with glucagon (20nM) for 6h. The cells were randomly divided into five experimental groups: (i) control group; (ⅱ) CGA group: cells were treated with 2μM chlorogenic acid for 24h; (iii) FA group: cells were treated with 2μM ferulic acid for 24h; (iv) PA group: cells were treated with 250μM Palmitic acid for 24h; (ⅴ) PA+Adomeglivant group: cells were incubated with 2μM Adomeglivant and 250μM Palmitic acid for 24 hours. Cells were digested with trypsin and incubated with 3% bovine serum albumin (BSA) for 15min on ice and then incubated with mouse anti-ceramide primary antibody (1:100 diluted in 0.1% BSA/PBS) for 45min at 4°C, followed by incubation with anti-mouse secondary antibody (1:100 diluted in 0.1% BSA/PBS) for 30min at 4°C in the dark. The primary and secondary antibody incubation steps were omitted for negative controls. After washing with cold PBS, ceramide levels were measured using flow cytometry at an excitation wavelength of 590nm and an emission wavelength of 617nm. |
Reaction Conditions | 2µM; 24h |
Applications | Adomeglivant treatment significantly reduced ceramide levels in the glucagon receptor-overexpressing H9c2 cells in response to glucagon stimulation. |
| Animal experiment [2]: | |
Animal models | Male C57BL/6 mice |
Preparation Method | Male C57BL/6 mice aged 6-9 months were housed in a conventional animal house with a light/dark cycle of 12h/12h, temperature of 22.2 to 22.7°C, humidity of 30 to 70%, and access to water and food ad libitum. Mice were trained (treadmill training) 1h a day, 5 times a week for 2 weeks at a speed of 17cm/s and a slope of 5°. Mice received a weekly intraperitoneal injection of the Adomeglivant at a dose of 2mg/kg/week during exercise. After 2 weeks, mouse islets were collected for analysis. |
Dosage form | 2mg/kg/week for 2 weeks; i.p. |
Applications | Adomeglivant treatment blocked AMPK activation and decreased the phosphorylation of the ACC and Rapto proteins (AMPK targets) in the islets of mice. |
References: | |
| Cas No. | 1488363-78-5 | SDF | |
| 别名 | 阿度格列凡; LY2409021 | ||
| Canonical SMILES | O=C(O)CCNC(C1=CC=C([C@@H](OC2=CC(C)=C(C3=CC=C(C(C)(C)C)C=C3)C(C)=C2)CCC(F)(F)F)C=C1)=O | ||
| 分子式 | C32H36F3NO4 | 分子量 | 555.63 |
| 溶解度 | DMSO : ≥ 5.6 mg/mL (10.08 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.7998 mL | 8.9988 mL | 17.9976 mL |
| 5 mM | 360 μL | 1.7998 mL | 3.5995 mL |
| 10 mM | 180 μL | 899.9 μL | 1.7998 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
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2.
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