Tejima Manabu, Hashimoto Tomoko, Ohno Osamu, Hoshina Tomoyuki, Takasaki Kotaro, Taniguchi Shintaro, Nakamura Kanako, Wei Fan-Yan, Tomizawa Kazuhito, Matsuno Kenji
Laboratory of Medicinal Chemistry, Department of Chemistry and Life Science, School of Advanced Engineering, Kogakuin University, 2665-1 Nakano-machi, Hachi-oji, Tokyo 192-0015, Japan.
Faculty of Pharmaceutical Sciences, Teikyo Heisei University, 4-21-2 Nakano, Nakano-ku, Tokyo 164-8530, Japan.
ACS Med Chem Lett. 2025 Jan 17;16(2):311-316. doi: 10.1021/acsmedchemlett.4c00560. eCollection 2025 Feb 13.
Cdk5 regulatory associated protein 1-like 1 () is one of the most reliable risk genes for type 2 diabetes mellitus (T2DM). Because controls glucose-induced insulin secretion by K channel responsiveness and faithful decoding of Lys codons to prevent mistranslation in pancreatic β-cells, a rescuer of defects is expected as a new antidiabetes drug. We found that eperisone analogs effectively rescued mistranslation in a -deficient dual-luciferase reporter gene system ( is a prokaryotic homologue of eukaryotic ). Among them, compounds and demonstrated significant antihyperglycemic efficacy in an oral glucose tolerance test by subcutaneous administration in Wister rats, along with a significant enhancement of insulin secretion in the MIN6 insulinoma cell line without cytotoxicity. These results indicate that could be a viable molecular target for a new anti-T2DM medication.
细胞周期蛋白依赖性激酶5调节相关蛋白1样1()是2型糖尿病(T2DM)最可靠的风险基因之一。由于通过钾通道反应性和对赖氨酸密码子的准确解码来控制葡萄糖诱导的胰岛素分泌,以防止胰腺β细胞中的错误翻译,因此有望找到一种缺陷的挽救剂作为新型抗糖尿病药物。我们发现,埃哌立松类似物在缺乏的双荧光素酶报告基因系统(是真核生物的原核同源物)中有效地挽救了错误翻译。其中,化合物和在Wister大鼠中通过皮下给药在口服葡萄糖耐量试验中显示出显著的抗高血糖功效,同时在MIN6胰岛素瘤细胞系中胰岛素分泌显著增强且无细胞毒性。这些结果表明,可能是新型抗T2DM药物的可行分子靶点。