Dipeptidylpeptidase 4 (DPP4) belongs to the S9b gene family of postproline serine peptidases. It acts mostly as a secreted membrane protein, mediating the degradation and inactivation of glucagon-like peptide (GLP)-1 and gastric inhibitory protein (GIP)[3]. Trelagliptin succinate, a novel DPP4 inhibitor, shows sustained efficacy by once-weekly dosing in type 2 diabetes patients and it exhibits >10,000-fold selectivity over related proteases including DPP8 and DPP9. Trelagliptin exhibited potent inhibitory activity toward DPP4 prepared from Caco-2 cells with an IC50 value of 5.4 nM. It also inhibited human, dog, and rat plasma DPP4 activity with IC50 values of 4.2, 6.2, and 9.7 nM respectively. In a phase 2 dose-ranging study using a sigmoid Emax model, the plasma trelagliptin concentration estimated to yield 50% and 70% inhibition of plasma DPP4 activity was 1.43 ng/mL and 2.31 ng/mL, respectively[4].
作用机制
The aminopiperidine forms a salt bridge to Glu205/Glu206, while the cyanobenzyl group effectively fills the S1 pocket and interacts with Arg125.
Trelagliptin succinate/琥珀酸曲格列汀 细胞实验
Cell Line
Concentration
Treated Time
Description
References
MC3T3-E1 cells
50 µM
14 days
Trelagliptin enhanced the differentiation and mineralization of MC3T3-E1 cells, upregulated the expression of ALP, OCN, OPN, and BMP-2, and increased the expression of RUNX2.
Bioengineered. 2021 Dec;12(1):960-968
Trelagliptin succinate/琥珀酸曲格列汀 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Sprague-Dawley rats
Diabetic rat model
Oral gavage
40 mg/kg
Once weekly for three months
To evaluate the effects of Trelagliptin on memory function in diabetic rats. Results showed that Trelagliptin improved fear memory deficits, reduced neuronal cell death in the cerebral cortex, and activated the AMPK/AKT/GSK-3β pathway.
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