Global Drug R&D Center, Huadong Medicine Company Limited, Hangzhou 310011, P. R. of China.
J Med Chem. 2024 Sep 12;67(17):14820-14839. doi: 10.1021/acs.jmedchem.4c01177. Epub 2024 Aug 14.
Various small molecule GLP1R agonists have been developed and tested for treating type 2 diabetes (T2DM) and obesity. However, many of these new compounds have drawbacks, such as potential hERG inhibition, lower activity compared to natural GLP-1, limited oral bioavailability in cynomolgus monkeys, and short duration of action. Recently, a new category of 3-phenyloxetane derivative GLP1R agonists with enhanced hERG inhibition has been discovered. Using an AIDD/CADD method, compound () was identified as a potent and selective GLP1R agonist, which was chosen as a preclinical candidate (PCC). Compound demonstrates full agonistic efficacy in promoting cAMP accumulation and possesses favorable drug-like characteristics compared to the clinical drug candidate Danuglipron. Additionally, in hGLP-1R knock-in mice, compound displayed a sustained pharmacological effect, effectively reducing blood glucose levels and food intake. These findings suggest that compound holds promise as a future treatment option for T2DM and obesity, offering improved properties.
各种小分子 GLP1R 激动剂已被开发并测试用于治疗 2 型糖尿病（T2DM）和肥胖症。然而，许多这些新化合物具有缺点，例如潜在的 hERG 抑制作用，与天然 GLP-1 相比活性较低，在食蟹猴中的口服生物利用度有限，以及作用持续时间短。最近，发现了一类具有增强 hERG 抑制作用的新型 3-苯氧恶烷衍生物 GLP1R 激动剂。使用 AIDD/CADD 方法，鉴定出化合物 () 是一种强效和选择性的 GLP1R 激动剂，被选为临床前候选药物（PCC）。化合物 在促进 cAMP 积累方面表现出完全激动剂的功效，与临床候选药物 Danuglipron 相比具有良好的类药性特征。此外，在 hGLP-1R 基因敲入小鼠中，化合物 显示出持续的药理作用，有效降低血糖水平和食物摄入。这些发现表明，化合物 作为 T2DM 和肥胖症的未来治疗选择具有潜力，提供了改进的特性。
