MK 0893 is a potent and selective glucagon receptor (GCGR) antagonist with an IC50 value of 6.6 nM[1]. The mechanism of action of MK 0893 is to prevent GCGR activation by limiting the movement of transmembrane helix 6 (TM6) protein required for G protein signaling [2]. MK-0893 treats patients with type 2 diabetes and effectively reduces postprandial blood sugar, but it will cause an increase in liver transaminases and is not suitable for clinical development [3].
In vitro, MK 0893 (0-1000nM) treated human primary liver cells for 1 hour, inhibited the effect of glucagon and prevented it from inducing the production of cAMP, with an IC50 value of 563nM [4]. MK 0893 (0-400nM) treated INS-1 832/13 cells and inhibited the effects of glucagon and also inhibited the effects of glucagon-like peptide-1 (GLP-1) [5].
In vivo, oral administration of MK 0893 (3, 10 mg/kg) to hGCGR ob/ob mice reduced blood glucose levels by 32% and 39% at single doses of 3 and 10 mg/kg, respectively [1]. MK 0893 (3, 10 mg/kg) administered orally to WT and hGCGR mice did not significantly affect plasma cholesterol or plant sterol levels in WT mice, however, at a dose of 10 mg/kg, it significantly increased campesterol levels. In hGCGR mice, MK 0893 exhibited a dose-dependent increase in plasma sitosterol levels [4].
References:
[1] Xiong Y, Guo J, Candelore M R, et al. Discovery of a Novel Glucagon Receptor AntagonistN-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1 H-pyrazol-1-yl] ethyl} phenyl) carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes[J]. Journal of medicinal chemistry, 2012, 55(13): 6137-6148.
[2] Crunkhorn S. Glucagon receptor antagonist binding site identified[J]. Nature Reviews Drug Discovery, 2016, 15(6): 384-384.
[3] Christensen M, Bagger J I, Vilsboll T, et al. The alpha-cell as target for type 2 diabetes therapy[J]. The review of diabetic studies: RDS, 2011, 8(3): 369.
[4] Guan H P, Yang X, Lu K, et al. Glucagon receptor antagonism induces increased cholesterol absorption [S][J]. Journal of lipid research, 2015, 56(11): 2183-2195.
[5] 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.
MK 0893是一种有效，选择性的胰高血糖素受体（GCGR，glucagon receptor）拮抗剂，IC50 值为6.6 nM[1]。 MK 0893的作用机制是通过限制G蛋白信号传导所需的跨膜螺旋6（TM6）蛋白运动来防止GCGR激活[2]。MK-0893治疗2 型糖尿病患者，有效降低餐后血糖，但会造成肝脏转氨酶指标升高而不适用于临床开发[3]。
在体外，MK 0893（0-1000nM）处理人原代肝细胞1 h，抑制了胰高血糖素的作用，阻止其诱导cAMP的产生，IC50 值为563nM[4]。MK 0893（0-400nM）处理INS-1 832/13细胞，抑制了胰高血糖素的作用，还抑制了胰高血糖素样肽-1（GLP-1）的作用[5]。
在体内，MK 0893（3，10mg/kg）通过口服给药治疗hGCGR ob/ob小鼠，在3 和10mg/kg单剂量下分别使血糖水平降低了32%和39%[1]。MK 0893（3，10mg/kg）通过口服给药治疗WT和hGCGR小鼠，对WT小鼠的血浆胆固醇或植物甾醇水平没有显著影响，但在10mg/kg时显著增加了菜油甾醇水平，对hGCGR小鼠的血浆谷甾醇水平呈剂量依赖性增加趋势[4]。