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 42 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, 42 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.

中文翻译：

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发现新型 5,6-二氢-1,2,4-三嗪衍生物作为有效的胰高血糖素样肽-1 受体激动剂

Danuglipron是最具代表性的胰高血糖素样肽-1受体（GLP-1R）小分子激动剂，因临床试验中治疗2型糖尿病（T2DM）和肥胖症的积极结果而受到广泛关注。然而，hERG 抑制、比内源性 GLP-1 更低的活性以及短的作用时间代表了可行应用方面的限制。在这项研究中，我们报道了一类新的 5,6-二氢-1,2,4-三嗪衍生物，其用于消除由 danuglipron 哌啶环引起的潜在 hERG 抑制。将系统的体外筛选应用于体内筛选，我们鉴定了化合物42作为一种高效、选择性的 GLP-1R 激动剂，与 danuglipron 相比，它在刺激 cAMP 积累方面具有更高的功效（7 倍），并且表现出可接受的药物样特性。此外，42显着降低 hGLP-1R Knock-In 小鼠的葡萄糖偏移并抑制食物摄入。这些作用比 danuglipron 所显示的效果更持久，证明了治疗 T2DM 和肥胖症的可行性。