Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
Biochem Biophys Res Commun. 2010 Nov 12;402(2):280-5. doi: 10.1016/j.bbrc.2010.10.015. Epub 2010 Oct 16.
G protein-coupled receptor (GPR) 119 is highly expressed in pancreatic β-cells and enhances the effect of glucose-stimulated insulin secretion (GSIS) on activation. The development of an oral GPR119 agonist that specifically targets the first phase of GSIS represents a promising strategy for the treatment of type 2 diabetes. In the present study, we evaluated the therapeutic potential of a novel small molecule GPR119 agonist, AS1535907, which was modified from the previously identified 2,4,6-tri-substituted pyrimidine core agonist AS1269574. AS1535907 displayed an EC50 value of 4.8 μM in HEK293 cells stably expressing human GPR119 and stimulated insulin secretion in rat islets only under high-glucose (16.8 mM) conditions. In isolated perfused pancreata from normal rats, AS1535907 enhanced the first phase of insulin secretion at 16.8 mM glucose, but had no effect at 2.8mM glucose. In contrast, the sulfonylurea glibenclamide predominantly induced insulin release in the second phase at 16.8 mM glucose and also markedly stimulated insulin secretion at 2.8 mM glucose. In in vivo studies, a single 10 μM administration of AS1535907 to diabetic db/db mice reduced blood glucose levels due to the rapid secretion of insulin secretion following oral glucose loading. These results demonstrate that GPR119 agonist AS1535907 has the ability to stimulate the first phase of GSIS, which is important for preventing the development of postprandial hypoglycemia. In conclusion, the GPR119 agonist AS1535907 induces a more rapid and physiological pattern of insulin release than glibenclamide, and represents a novel strategy for the treatment of type 2 diabetes.
G 蛋白偶联受体 (GPR) 119 在胰腺 β 细胞中高度表达，并增强葡萄糖刺激的胰岛素分泌 (GSIS) 的激活效应。开发一种专门针对 GSIS 第一相的口服 GPR119 激动剂，代表了治疗 2 型糖尿病的一种有前途的策略。在本研究中，我们评估了一种新型小分子 GPR119 激动剂 AS1535907 的治疗潜力，该激动剂是从先前鉴定的 2,4,6-三取代嘧啶核心激动剂 AS1269574 中修改而来的。AS1535907 在稳定表达人 GPR119 的 HEK293 细胞中的 EC50 值为 4.8 μM，仅在高葡萄糖 (16.8 mM) 条件下刺激大鼠胰岛胰岛素分泌。在正常大鼠分离的灌注胰腺中，AS1535907 在 16.8 mM 葡萄糖下增强胰岛素分泌的第一相，但在 2.8 mM 葡萄糖下没有作用。相比之下，磺酰脲类药物格列本脲主要在 16.8 mM 葡萄糖的第二相诱导胰岛素释放，并且在 2.8 mM 葡萄糖下也显著刺激胰岛素分泌。在体内研究中，单次给予 10 μM 的 AS1535907 可降低糖尿病 db/db 小鼠的血糖水平，这是由于口服葡萄糖负荷后胰岛素分泌迅速。这些结果表明，GPR119 激动剂 AS1535907 具有刺激 GSIS 第一相的能力，这对于预防餐后低血糖的发展很重要。总之，GPR119 激动剂 AS1535907 诱导的胰岛素释放模式比格列本脲更快更生理，代表了治疗 2 型糖尿病的一种新策略。
