Han Taedong, Lee Byoung Moon, Park Yoo Hoi, Lee Dong Hoon, Choi Hyun Ho, Lee Taehoon, Kim Hakwon
Department of Applied Chemistry and Global Center for Pharmaceutical Ingredient Materials, Kyung Hee University, Yongin 17104, Republic of Korea.
Yuhan R&D Institute, Yongin 17084, Republic of Korea.
Biomol Ther (Seoul). 2018 Mar 1;26(2):201-209. doi: 10.4062/biomolther.2018.011.
G protein-coupled receptor 119 (GPR119) is expressed in the pancreas and gastrointestinal tract, and its activation promotes insulin secretion in the beta cells of the pancreatic islets as well as the secretion of glucagon-like peptide-1 (GLP-1) in intestinal L cells, consequently improving glucose-stimulated insulin secretion. Due to this dual mechanism of action, the development of small-molecule GPR119 agonists has received significant interest for the treatment of type 2 diabetes. We newly synthesized 1,2,4-triazolone derivatives of GPR119 agonists, which demonstrated excellent outcomes in a cyclic adenosine monophosphate (cAMP) assay. Among the synthesized derivatives, YH18968 showed cAMP=2.8 nM; in GLUTag cell, GLP-1secretion=2.3 fold; in the HIT-T15 cell, and insulin secretion=1.9 fold. Single oral administration of YH18968 improved glucose tolerance and combined treatment with a dipeptidyl peptidase 4 (DPP-4) inhibitor augmented the glucose lowering effect as well as the plasma level of active GLP-1 in normal mice. Single oral administration of YH18968 improved glucose tolerance in a diet induced obese mice model. This effect was maintained after repeated dosing for 4 weeks. The results indicate that YH18968 combined with a DPP-4 inhibitor may be an effective therapeutic candidate for the treatment of type 2 diabetes.
G蛋白偶联受体119（GPR119）在胰腺和胃肠道中表达，其激活可促进胰岛β细胞分泌胰岛素以及肠道L细胞分泌胰高血糖素样肽-1（GLP-1），从而改善葡萄糖刺激的胰岛素分泌。由于这种双重作用机制，小分子GPR119激动剂的开发在2型糖尿病治疗方面受到了广泛关注。我们新合成了GPR119激动剂的1,2,4-三唑啉酮衍生物，其在环磷酸腺苷（cAMP）测定中显示出优异的结果。在合成的衍生物中，YH18968的cAMP为2.8 nM；在GLUTag细胞中，GLP-1分泌增加2.3倍；在HIT-T15细胞中，胰岛素分泌增加1.9倍。在正常小鼠中，单次口服YH18968可改善葡萄糖耐量，与二肽基肽酶4（DPP-4）抑制剂联合治疗可增强降糖效果以及活性GLP-1的血浆水平。在饮食诱导的肥胖小鼠模型中，单次口服YH18968可改善葡萄糖耐量。重复给药4周后，这种效果得以维持。结果表明，YH18968与DPP-4抑制剂联合使用可能是治疗2型糖尿病的有效候选药物。
