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

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

  • Eur J Pharmacol. 2016 Oct 5;788:54-64. doi: 10.1016/j.ejphar.2016.06.016.
Sung-Ho Kim 1 Eunsoo Jung 2 Min Kyung Yoon 2 O Hwan Kwon 2 Dal-Mi Hwang 2 Dong-Wook Kim 2 Junghyun Kim 3 Sun-Mee Lee 4 Hyeon Joo Yim 5
Affiliations

Affiliations

  • 1 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.
  • 2 LG Life Sciences Ltd., R&D Park, Daejeon 34122, Republic of Korea.
  • 3 Korean Medicine Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea.
  • 4 School of Pharmacy, Sungkyunkwan University, Seobu-ro 2066, Jangan-gu, Suwon, Gyeonggi-do 16419, Republic of Korea.
  • 5 LG Life Sciences Ltd., R&D Park, Daejeon 34122, Republic of Korea. Electronic address: hjyim@lgls.com.
Abstract

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.

Keywords

Dipeptidyl peptidase-4 inhibitor; Gemigliptin; Gemigliptin (PubChem CID: 11953153); Incretin; Sitagliptin (PubChem CID: 11591741); Type 2 diabetes mellitus; Vildagliptin (PubChem CID: 11077541).

Figures
Products