Animal experiment:

Rats[1] Nine-week-old Wistar rats are randomly divided into 13 groups of eight animals each based on body weight (306.2-374.2 g) and plasma DPP-4 activity. Teneligliptin (MP-513) is orally administered to four groups (0.01, 0.1, 1 and 10 mg/2 mL/kg). Sitagliptin and vildagliptin is orally administered to each four groups (0.1, 1, 10 and 100 mg/kg). Vehicle (0.5% hydroxypropyl methylcellulose) is orally administered to one group. Blood samples are collected from the tail vein with heparinized capillary tubes at 0 h (pre dose) and 0.5, 1, 2, 3, 6, 9, 12, and 24 h (post dose) and centrifuged at 1800 g for 15 min at 4℃. Separated plasma is used for the measurement of DPP-4 activity. For dose-response curve using the maximum effect in each dose, the dose of the inhibitors which produce half of the maximum effect; ED50 are calculated. Mice[2] Monosodium glutamate (MSG) is administered into the neonatal ICR mice at birth as a single-dose subcutaneous injection (4 mg/g body weight). Among these mice, males are divided into two groups at 4 weeks of age: the MSG/HFD group (n=6, Group 1) and the MSG/HFD/Teneligliptin (MP-513)-treated group (n=6, Group 2). The mice in Group 2 are administered Teneligliptin (MP-513) (30 mg/kg per day) in the drinking water from 4 weeks of age. The treatment dose of Teneligliptin (MP-513) is determined according to the data from the animal experiments in the drug development process. Although the dose is relatively higher than that for humans in clinical practice, no notable adverse effect is observed in the treatment with the dose for the experimental animal in the process. Both groups are fed HFD from 4-14 weeks of age. At the termination of the experiment (14 weeks of age), all animals are sacrificed by CO2 asphyxiation to analyze hepatic histopathology.

Teneligliptin hydrobromide is a novel, potent, and long-lasting dipeptidyl peptidase-4 (DPP-4) inhibitor with antioxidant properties; competitively inhibited human plasma, rat plasma, and human recombinant DPP-4 in vitro, with IC50 values of about 1 nM[1].

DPP4 is also known as adenosine deaminase complexing protein 2 or CD26. DPP4 is an antigenic enzyme expressed on the membrane of most cell types and is associated with immune regulation, signal transduction and apoptosis [2].

In vitro: In human umbilical vein endothelial cells, Teneligliptin promoted the antioxidant response, reduced ROS levels and induced Nrf2-target genes messenger ribonucleic acid expression. Teneligliptin improved proliferation rates in HUVECs exposed to high glucose, regulating the expression of cell-cycle inhibitors markers (P21, P53 and P27), and reducing proapoptotic genes (BAX and CASP3), while promoteed BCL2 expression. Teneligliptin ameliorated high glucose-induced endoplasmic reticulum stress. Teneligliptin exihibited antioxidant properties and overcome the metabolic memory effect induced by chronic exposure to high glucose in HUVECs[3].

In vivo:In teneligliptin-treated mice, serum alanine aminotransferase and intrahepatic triglyceride levels were significantly decreased (p< 0.05). Teneligliptin also significantly downregulated hepatic mRNA levels of the genes involved in de novo lipogenesis (p< 0.05). Moreover, The hepatic expression levels of phosphorylated AMP-activated protein kinase (AMPK) protein were upregulated by teneligliptin[4]. Orally administration of teneligliptin at a dosage of 20 mg once daily in adults in the ovariectomized (OVX) mice maintained on a high-fat diet, teneligliptin effectively ameliorated the characteristics of metabolic abnormalities associated with postmenopausal obesity. Teneligliptin ameliorated the decreased energy consumption in the dark and light phases, reduced locomotor activity in the dark phase, and lowered core body temperature in OVX-HF[5].

References:
[1] Kishimoto M.  Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes[J]. Diabetes, metabolic syndrome and obesity: targets and therapy, 2013, 6: 187.
[2] Kameoka J, Tanaka T, Nojima Y, et al.  Direct association of adenosine deaminase with a T cell activation antigen, CD26[J]. Science, 1993, 261(5120): 466-469.
[3] Pujadas G, De Nigris V, Prattichizzo F, et al.  The dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin functions as antioxidant on human endothelial cells exposed to chronic hyperglycemia and metabolic high-glucose memory[J]. Endocrine, 2016: 1-12.
[4] Ideta T, Shirakami Y, Miyazaki T, et al.  The Dipeptidyl Peptidase-4 Inhibitor Teneligliptin Attenuates Hepatic Lipogenesis via AMPK Activation in Non-Alcoholic Fatty Liver Disease Model Mice[J]. International journal of molecular sciences, 2015, 16(12): 29207-29218.
[5] Sameshima A, Wada T, Ito T, et al.  Teneligliptin improves metabolic abnormalities in a mouse model of postmenopausal obesity[J]. Journal of Endocrinology, 2015, 227(1): 25-36.