DA-1229, a novel and potent DPP4 inhibitor, improves insulin resistance and delays the onset of diabetes

• Published in: Life sciences (1973) 2012-01, Vol.90 (1), p.21-29
• Main Authors: Kim, Mi-Kyung, Chae, Yu Na, Kim, Ha Dong, Yang, Eun Kyoung, Cho, Eun Jung, Choi, Song-hyen, Cheong, Ye-Hwang, Kim, Hae-Sun, Kim, Heung Jae, Jo, Yeong Woo, Son, Moon-Ho, Kim, Soon-Hoe, Shin, Chang Yell
• Format: Article
• Language: English
• Subjects: Animals; blood glucose; CHO Cells; Cricetinae; Cricetulus; DA-1229; Db/db mice; diabetes; Diabetes Mellitus - blood; Diabetes Mellitus - drug therapy; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl peptidase 4 inhibitor; Dipeptidyl-Peptidase IV Inhibitors - chemistry; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; enzyme inhibition; Glucagon-like peptide-1; glucose; glycemic effect; High fat diet-fed mice; Humans; Hypoglycemic Agents - therapeutic use; inhibitory concentration 50; insulin; Insulin resistance; Insulin Resistance - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Onset of diabetes; Piperazines - chemistry; Piperazines - therapeutic use; Random Allocation; Time Factors; weight loss
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2011.10.007

To characterize the pharmacodynamic profile of DA-1229, a novel dipeptidyl peptidase (DPP) 4 inhibitor. Enzyme inhibition assays against DPP4, DPP8 and DPP9. Antidiabetic effects of DA-1229 in HF-DIO mice and young db/db mice. DA-1229 was shown to potently inhibit the DPP4 enzyme in human and murine soluble forms and the human membrane-bound form with IC 50 values of 0.98, 3.59 and 1.26 nM, respectively. As a reversible and competitive inhibitor, DA-1229 was more selective to human DPP4 (6000-fold) than to human DPP8 and DPP9. DA-1229 (0.1–3 mg/kg) dose-dependently inhibited plasma DPP4 activity, leading to increased levels of plasma GLP-1 and insulin, and thereby lowering blood glucose levels in mice. In high fat diet-fed (HF) mice, a single oral dose of 100 mg/kg of DA-1229 reduced plasma DPP4 activity by over 80% during a 24 h period. Long-term treatment with DA-1229 for 8 weeks revealed significant improvements in glucose intolerance and insulin resistance, accompanied by significant body weight reduction. However, it remains unclear whether there is a direct causal relationship between DPP4 inhibition and body weight reduction. In young db/db mice, the DA-1229 treatment significantly reduced blood glucose excursions for the first 2 weeks, resulting in significantly lower levels of HbA1c at the end of the study. Furthermore, the pancreatic insulin content of the treatment group was significantly higher than that of the db/db control. DA-1229 as a novel and selective DPP4 inhibitor improves the insulin sensitivity in HF mice and delays the onset of diabetes in young db/db mice.