Drug Discovery Research, Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan.
Life Sci. 2013 Feb 7;92(2):167-73. doi: 10.1016/j.lfs.2012.11.015. Epub 2012 Dec 13.
G-protein-coupled receptor 119 (GPR119), mainly expressed in pancreatic β-cells, represents a new target for treating type 2 diabetes. GPR119 agonist is known to induce insulin secretion in a glucose-dependent manner by elevating intracellular cAMP concentrations. This study mainly examined the anti-hyperglycemic effect of a novel candidate small-molecule GPR119 agonist AS1669058 2-(4-bromo-2,5-difluorophenyl)-6-methyl-N-[2-(1-oxidopyridin-3-yl)ethyl]pyrimidin-4-amine ethanedioate on ICR mice and diabetic db/db mice.
We measured blood glucose, plasma insulin, and insulin content in the pancreas after repeated administration of AS1669058 to db/db mice twice daily for one week.
Under high-concentration glucose conditions, AS1669058 induced insulin secretion in a dose-dependent manner in the hamster pancreatic β-cell line HIT-T15 and in rat pancreatic islets. In addition, AS1669058 increased human insulin promoter activity in NIT-1 cells. In in vivo studies, a single administration of AS1669058 (1 mg/kg) in ICR mice improved oral glucose tolerance based on insulin secretion. Further, 1-week repeated treatment (3 mg/kg, twice daily) in diabetic db/db mice significantly reduced blood glucose levels and tended to increase insulin content in the pancreas.
These results suggest that AS1669058 has promising potential as an extremely more effective anti-hyperglycemic agent than other compounds we previously reported as GPR119 agonists.
G 蛋白偶联受体 119（GPR119）主要在胰岛β细胞中表达，是治疗 2 型糖尿病的新靶点。已知 GPR119 激动剂通过升高细胞内 cAMP 浓度以葡萄糖依赖的方式诱导胰岛素分泌。本研究主要考察了新型小分子 GPR119 激动剂 AS1669058（2-（4-溴-2,5-二氟苯基）-6-甲基-N-（2-（1-氧化吡啶-3-基）乙基）嘧啶-4-胺乙二酸盐）对 ICR 小鼠和糖尿病 db/db 小鼠的抗高血糖作用。
我们测量了 db/db 小鼠每天两次重复给予 AS1669058 一周后血糖、血浆胰岛素和胰腺胰岛素含量。
在高浓度葡萄糖条件下，AS1669058 以剂量依赖方式诱导仓鼠胰岛β细胞系 HIT-T15 和大鼠胰岛胰岛素分泌。此外，AS1669058 增加了 NIT-1 细胞中人胰岛素启动子活性。在体内研究中，AS1669058（1mg/kg）单次给药改善了 ICR 小鼠的口服葡萄糖耐量，这基于胰岛素分泌。此外，糖尿病 db/db 小鼠 1 周重复治疗（3mg/kg，每天两次）显著降低了血糖水平，并倾向于增加胰腺中的胰岛素含量。
这些结果表明，AS1669058 作为一种抗高血糖剂具有很大的潜力，比我们之前报道的其他作为 GPR119 激动剂的化合物更为有效。
