Chen Lili, Yun Ying, Guo Shimeng, Wang Xiaoyan, Xiong Muya, Zhao Tingting, Xu Tifei, Shen Jianhua, Xie Xin, Wang Kai
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
J Med Chem. 2023 Jun 22;66(12):7988-8010. doi: 10.1021/acs.jmedchem.3c00320. Epub 2023 Jun 7.
Danuglipron is the most representative small-molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R) and has received considerable attention due to positive results in the treatment of type 2 diabetes mellitus (T2DM) and obesity in clinical trials. However, hERG inhibition, lower activity than endogenous GLP-1, and a short action time represent limitations in terms of feasible application. In this study, we report a new class of 5,6-dihydro-1,2,4-triazine derivatives that serve to eliminate potential hERG inhibition caused by the piperidine ring of danuglipron. Applying systematic in vitro to in vivo screening, we have identified compound as a highly potent and selective GLP-1R agonist, which delivers improved (7-fold) efficacy in stimulating cAMP accumulation compared with danuglipron and which exhibits acceptable drug-like properties. Furthermore, significantly reduces glucose excursion and inhibits food intake of hGLP-1R Knock-In mice. These effects are longer-lasting than that shown by danuglipron, demonstrating feasibility in the treatment of T2DM and obesity.
达努格列净是胰高血糖素样肽-1受体（GLP-1R）最具代表性的小分子激动剂，由于在2型糖尿病（T2DM）和肥胖症治疗的临床试验中取得了积极成果而备受关注。然而，人乙醚相关基因（hERG）抑制、活性低于内源性GLP-1以及作用时间短等问题限制了其实际应用。在本研究中，我们报道了一类新型的5,6-二氢-1,2,4-三嗪衍生物，该衍生物可消除达努格列净哌啶环引起的潜在hERG抑制。通过系统的体外到体内筛选，我们确定化合物为一种高效且选择性的GLP-1R激动剂，与达努格列净相比，其在刺激环磷酸腺苷（cAMP）积累方面的效力提高了7倍，并且具有可接受的类药性质。此外，该化合物可显著降低血糖波动，并抑制人GLP-1受体基因敲入（hGLP-1R Knock-In）小鼠的食物摄入量。这些作用比达努格列净更持久，证明了其在治疗T2DM和肥胖症方面的可行性。
