Type 2 diabetes mellitus (T2DM) is a chronic, complex and multifactorial metabolic disorder, and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. This study discovered a new class of thieno[2,3-b]pyridine derivatives as hepatic gluconeogenesis inhibitors. First, a hit compound (DMT: IC₅₀ = 33.8 μM) characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. Structure activity relationships (SARs) study showed that replaced the CF₃ in the thienopyridine core could improve the potency and led to the discovery of 8e (IC₅₀ = 16.8 μM) and 9d (IC₅₀ = 12.3 μM) with potent inhibition of hepatic glucose production and good drug-like properties. Furthermore, the mechanism of 8e for the inhibition of hepatic glucose production was also identified, which could be effective through the reductive expression of the mRNA transcription level of gluconeogenic genes, including glucose-6-phosphatase (G6Pase) and hepatic phosphoenolpyruvate carboxykinase (PEPCK). Additionally, 8e could also reduce the fasting blood glucose and improve the oral glucose tolerance and pyruvate tolerance in db/db mice. The optimization of this class of derivatives had provided us a start point to develop new anti-hepatic gluconeogenesis agents.

2型糖尿病（T2DM）是一种慢性，复杂和多因素的代谢性疾病，靶向抑制糖异生是抗糖尿病药物发现的一种有前途的策略。这项研究发现了一类新的噻吩并[2,3- b ]吡啶衍生物作为肝糖异生抑制剂。首先， 在我们特权的小分子文库的基于细胞的筛选中，鉴定了以噻吩并吡啶核为特征的命中化合物（DMT：IC ₅₀ = 33.8μM）。结构活性关系（SARs）研究表明，在噻吩并吡啶核中取代CF ₃可以提高效能，并导致发现8e（IC ₅₀  = 16.8μM）和9d（IC₅₀  = 12.3μM），可有效抑制肝葡萄糖生成，并具有良好的药物样特性。此外，还确定了8e抑制肝葡萄糖生成的机制，这可以通过还原性表达葡萄糖异生基因的mRNA转录水平而有效，这些基因包括葡萄糖6磷酸酶（G6Pase）和肝磷酸烯醇丙酮酸羧激酶（PEPCK）。 。此外，8e还可以降低db / db小鼠的空腹血糖并改善口服葡萄糖耐量和丙酮酸耐量。这类衍生物的优化为我们开发新的抗肝糖异生剂提供了一个起点。