Department of Pharmacology, Chongqing Medical University, the Key Laboratory of Biochemistry and Molecular Pharmacology, Chongqing 400016, China.
Sci Rep. 2017 Apr 13;7:46628. doi: 10.1038/srep46628.
Dipeptidyl peptidase IV (DPP-IV) inhibitor has been expected to be a new class of anti-diabetic agent. The present study was designed to characterize the pharmacological profiles of CMD-05, a novel DPP-IV inhibitor discovered in our laboratory, in vitro and in vivo. The IC of CMD-05 on DPP-IV inhibitory activity was approximately 12 nM while vildagliptin was 3.5 nM in vitro. In diabetes rat model established by high fat diet/low dose streptozotocin, CMD-05 inhibited DPP-IV activity, significantly improved glucose tolerance, increased GLP-1 and insulin levels in plasma. Long-term administration of CMD-05 decreased HbA1c and TG levels and improved the islet function without significantly effect on body weight. Furthermore, CMD-05 reduced INS-1 cell apoptosis and increased GLP-1 secretion in NCI-H716. After oral administration, CMD-05 reached peak concentration at 30 min with half-life of 288 minutes and the inhibitory rate of DPP-IV greater than 50% lasted for 15 h. In fasted normal rats, CMD-05 didn't cause significant hypoglycemia. CMD-05 had a lower cytotoxicity than vildagliptin in vitro and its maximum tolerance dose in mice is beyond 2000 mg/kg. These results indicated that CMD-05 has similar activity with vildagliptin in vivo and has a much longer half-life and lower cytotoxicity than vildagliptin.
二肽基肽酶 IV（DPP-IV）抑制剂有望成为一类新型的抗糖尿病药物。本研究旨在体外和体内研究我们实验室发现的新型 DPP-IV 抑制剂 CMD-05 的药理学特性。CMD-05 对 DPP-IV 抑制活性的 IC 约为 12 nM，而维格列汀为 3.5 nM。在高脂肪饮食/低剂量链脲佐菌素建立的糖尿病大鼠模型中，CMD-05 抑制 DPP-IV 活性，显著改善葡萄糖耐量，增加血浆中 GLP-1 和胰岛素水平。长期给予 CMD-05 可降低 HbA1c 和 TG 水平，改善胰岛功能，而对体重无明显影响。此外，CMD-05 可减少 INS-1 细胞凋亡并增加 NCI-H716 中的 GLP-1 分泌。口服给药后，CMD-05 在 30 分钟时达到峰值浓度，半衰期为 288 分钟，DPP-IV 的抑制率大于 50%持续 15 小时。在禁食的正常大鼠中，CMD-05 不会引起明显的低血糖。CMD-05 在体外的细胞毒性低于维格列汀，其在小鼠中的最大耐受剂量超过 2000 mg/kg。这些结果表明，CMD-05 在体内与维格列汀具有相似的活性，半衰期比维格列汀长，细胞毒性比维格列汀低。
