Open AccessCMD-05, a novel promising clinical anti-diabetic drug candidate, in vivo and vitro studies
Author(s) -
Jie Ma,
Huan Li,
Xiangnan Hu,
Yang Lü,
Qi Chen,
Congli Hu,
Zhihao Chen,
Xia Tian,
Yang Yang,
Ying Luo,
Run Gan,
Junqing Yang
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/srep46628
Subject(s) - vildagliptin , in vivo , hypoglycemia , endocrinology , pharmacology , ic50 , medicine , in vitro , diabetes mellitus , dipeptidyl peptidase 4 , streptozotocin , dipeptidyl peptidase , dipeptidyl peptidase 4 inhibitor , cytotoxicity , insulin , chemistry , type 2 diabetes , biology , biochemistry , enzyme , microbiology and biotechnology
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 50 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.