Pharmacological profiles of gemigliptin (LC15-0444), a novel dipeptidyl peptidase-4 inhibitor, in vitro and in vivo.
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.
LG Life Sciences Ltd., R&D Park, Daejeon 34122, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Seobu-ro 2066, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
Sung-Ho
SH
Kim
LG Life Sciences Ltd., R&D Park, Daejeon 34122, Republic of Korea.
Eunsoo
E
Jung
LG Life Sciences Ltd., R&D Park, Daejeon 34122, Republic of Korea.
Min Kyung
MK
Yoon
LG Life Sciences Ltd., R&D Park, Daejeon 34122, Republic of Korea.
O Hwan
OH
Kwon
LG Life Sciences Ltd., R&D Park, Daejeon 34122, Republic of Korea.
Dal-Mi
DM
Hwang
LG Life Sciences Ltd., R&D Park, Daejeon 34122, Republic of Korea.
Dong-Wook
DW
Kim
Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea.
Junghyun
J
Kim
School of Pharmacy, Sungkyunkwan University, Seobu-ro 2066, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
Sun-Mee
SM
Lee
LG Life Sciences Ltd., R&D Park, Daejeon 34122, Republic of Korea. Electronic address: hjyim@lgls.com.
Hyeon Joo
HJ
Yim
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005951:Glucose Tolerance Test; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D010881:Piperidones / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013379:Substrate Specificity
D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; C534891:LC15-0444; D010881:Piperidones; D011743:Pyrimidines; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4
Dipeptidyl peptidase-4 inhibitor; Gemigliptin; Gemigliptin (PubChem CID: 11953153); Incretin; Sitagliptin (PubChem CID: 11591741); Type 2 diabetes mellitus; Vildagliptin (PubChem CID: 11077541)