The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small-molecule GLP-1 receptor agonists. In this study, two series of new pyrimidine derivatives were designed and synthesized using an efficient route, and were evaluated in terms of GLP-1 receptor agonist activity. In the first series, novel pyrimidines substituted at positions 2 and 4 with groups varying in size and electronic properties were synthesized in a good yield (78–90%). In the second series, the designed pyrimidine templates included both urea and Schiff base linkers, and these compounds were successfully produced with yields of 77–84%. In vitro experiments with cultured cells showed that compounds 3a and 10a (10⁻¹⁵–10⁻⁹ M) significantly increased insulin secretion compared to that of the control cells in both the absence and presence of 2.8 mM glucose; compound 8b only demonstrated significance in the absence of glucose. These findings represent a valuable starting point for the design and discovery of small-molecule GLP-1 receptor agonists that can be administered orally.

肽胰高血糖素样肽-1（GLP-1）受体激动剂在治疗2型糖尿病方面的治疗成功激发了旨在开发口服可用小分子GLP-1受体激动剂的发现努力。在这项研究中，使用有效途径设计和合成了两个新的嘧啶衍生物系列，并根据GLP-1受体激动剂活性对其进行了评估。在第一个系列中，新颖的嘧啶在2和4位被大小和电子性质变化的基团取代，合成产率高（78-90％）。在第二个系列中，设计的嘧啶模板同时包含尿素和席夫碱连接基，这些化合物均以77-84％的产率成功制备。培养细胞的体外实验表明，这些化合物3a和10a（10 ^-15 –10 ^-9  M）与不存在和存在2.8 mM葡萄糖的对照细胞相比，胰岛素分泌显着增加；化合物8b仅在不存在葡萄糖的情况下显示出重要意义。这些发现代表了设计和发现可以口服的小分子GLP-1受体激动剂的宝贵起点。