Pharmacological profiles of gemigliptin (LC15-0444), a novel dipeptidyl peptidase-4 inhibitor, in vitro and in vivo

• Published in: European journal of pharmacology 2016-10, Vol.788, p.54-64
• Main Authors: Kim, Sung-Ho, Jung, Eunsoo, Yoon, Min Kyung, Kwon, O. Hwan, Hwang, Dal-Mi, Kim, Dong-Wook, Kim, Junghyun, Lee, Sun-Mee, Yim, Hyeon Joo
• Format: Article
• Language: English
• Subjects: Animals; Blood Glucose - metabolism; Diabetes Mellitus, Experimental - blood; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl peptidase-4 inhibitor; Dipeptidyl-Peptidase IV Inhibitors - metabolism; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Dogs; Gemigliptin; Gemigliptin (PubChem CID: 11953153); Glucagon-Like Peptide 1 - blood; Glucose Tolerance Test; Humans; Incretin; Kinetics; Male; Mice; Piperidones - metabolism; Piperidones - pharmacology; Piperidones - therapeutic use; Pyrimidines - metabolism; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rats; Sitagliptin (PubChem CID: 11591741); Substrate Specificity; Type 2 diabetes mellitus; Vildagliptin (PubChem CID: 11077541)
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2016.06.016

Gemigliptin, a novel dipeptidyl peptidase (DPP)-4 inhibitor, is approved for use as a monotherapy or in combination therapy to treat hyperglycemia in patients with type 2 diabetes mellitus. In this study, we investigated the pharmacological profiles of gemigliptin in vitro and in vivo and compared them to those of the other DPP-4 inhibitors. Gemigliptin was a reversible and competitive inhibitor with a Ki value of 7.25±0.67nM. Similar potency was shown in plasma from humans, rats, dogs, and monkeys. The kinetics of DPP-4 inhibition by gemigliptin was characterized by a fast association and a slow dissociation rate compared to sitagliptin (fast on and fast off rate) or vildagliptin (slow on and slow off rate). In addition, gemigliptin showed at least >23,000-fold selectivity for DPP-4 over various proteases and peptidases, including DPP-8, DPP-9, and fibroblast activation protein (FAP)-α. In the rat, dog, and monkey, gemigliptin showed more potent DPP-4 inhibitory activity in vivo compared with sitagliptin. In mice and dogs, gemigliptin prevented the degradation of active glucagon-like peptide-1 by DPP-4 inhibition, which improved glucose tolerance by increasing insulin secretion and reducing glucagon secretion during an oral glucose tolerance test. The long-term anti-hyperglycemic effect of gemigliptin was evaluated in diet-induced obese mice and high-fat diet/streptozotocin-induced diabetic mice. Gemigliptin dose-dependently decreased hemoglobin A1c (HbA1c) levels and ameliorated β-cell damage. In conclusion, gemigliptin is a potent, long-acting, and highly selective DPP-4 inhibitor and can be a safe and effective drug for the long-term treatment of type 2 diabetes.