We described the discovery and optimization of a novel series of pyrimidopyrimidine derivatives as G-protein coupled receptor 119 (GPR119) agonists against type 2 diabetes. Most designed compounds displayed significant GPR119 agonistic activities. Optimized analogues 15a and 21e exhibited highly potent agonistic activities with single digit EC₅₀ values (2.2 nM and 8.1 nM, respectively). Therefore, 15a and 21e were evaluated for their oral glucose tolerance test (oGTT) in C57BL/6N mice. Compound 15a reduced the blood glucose area of under curve from 0 to 2 h (AUC_0–2h) to 13.5% at the dose of 15 mg/kg comparing with Metformin reduced 18% of AUC_0–2h at the dose of 300 mg/kg.

我们描述了一系列新型的嘧啶嘧啶衍生物作为针对2型糖尿病的G蛋白偶联受体119（GPR119）激动剂的发现和优化。大多数设计的化合物显示出显着的GPR119激动活性。优化的类似物15a和21e表现出高度有效的激动活性，其EC ₅₀值为个位数（分别为2.2 nM和8.1 nM）。因此，在C57BL / 6N小鼠中评估了15a和21e的口服葡萄糖耐量测试（oGTT）。在剂量为15 mg / kg的情况下，化合物15a将曲线下的血糖面积从0降低至2 h（AUC _0–2h）至13.5％，而二甲双胍则降低18％的AUC在300 mg / kg的剂量下_0–2h。