National Key Laboratory of Macromolecular Drug Development and Manufacturing, School of Pharmaceutical Sciences and Food Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China.
School of Chemistry and Chemical Engineering, Liaocheng University, 1 Hunan Street, Liaocheng 252059, China.
Int J Mol Sci. 2024 Oct 25;25(21):11476. doi: 10.3390/ijms252111476.
Diabetes mellitus (DM) is a common metabolic disease that poses a severe threat to human health. Despite a range of therapeutic approaches, there remains a lack of effective and safe therapies with the existing drugs. Therefore, there is an urgent need to develop novel, effective, and safe therapeutic strategies for DM. Free fatty acid receptor 4 (FFAR4), also known as GPR120, is a member of the G protein-coupled receptor family, which has received considerable attention as an attractive new therapeutic target for treating DM. In the present study, based on the structure of TUG-891, which has excellent activity and selectivity, a series of novel FFAR4 agonists was designed by replacing the phenylpropanoic acid β position carbon atom with an oxygen atom, while replacing the linking oxymethylene with an amide-linking group. The target compounds were evaluated for FFAR4 agonistic activity, and the preferred compounds were evaluated for selectivity, oral glucose tolerance in normal ICR mice, antidiabetic activity in diet-induced obese (DIO) mice, pharmacokinetic properties in ICR mice and molecular modeling studies. The results showed that compound possessed excellent FFAR4 agonistic activity and selectivity, significantly improved glucose tolerance in normal ICR mice, lowered blood glucose and promoted insulin secretion in a dose-dependent manner in DIO mice, and showed favorable pharmacokinetic properties. These results indicate that compound may be a promising compound that deserves further structure-activity relationship and pharmacological studies for the development of antidiabetic drugs.
糖尿病（DM）是一种常见的代谢性疾病，严重威胁人类健康。尽管有多种治疗方法，但现有的药物缺乏有效和安全的治疗方法。因此，迫切需要开发新型、有效和安全的 DM 治疗策略。游离脂肪酸受体 4（FFAR4），也称为 GPR120，是 G 蛋白偶联受体家族的成员，作为治疗 DM 的一种有吸引力的新治疗靶点，受到了广泛关注。在本研究中，基于具有优异活性和选择性的 TUG-891 的结构，通过用氧原子取代苯丙酸的β位碳原子，同时用酰胺连接基团取代连接的亚甲基氧基，设计了一系列新型 FFAR4 激动剂。对目标化合物进行了 FFAR4 激动活性评价，优选化合物进行了选择性、正常 ICR 小鼠口服葡萄糖耐量、饮食诱导肥胖（DIO）小鼠抗糖尿病活性、ICR 小鼠药代动力学特性和分子建模研究。结果表明，化合物 具有优异的 FFAR4 激动活性和选择性，可显著改善正常 ICR 小鼠的葡萄糖耐量，以剂量依赖性方式降低 DIO 小鼠的血糖并促进胰岛素分泌，具有良好的药代动力学特性。这些结果表明，化合物 可能是一种有前途的化合物，值得进一步进行结构-活性关系和药理学研究，以开发抗糖尿病药物。
