Trelagliptin succinate

Trelagliptin succinate (CAS No. 1029877-94-8) is a long-acting selective dipeptidyl peptidase-4 (DPP-4) inhibitor. Its core biological functions include lowering blood glucose in type 2 diabetes mellitus (T2DM), improving insulin resistance, inhibiting inflammatory responses, protecting chondrocyte function, alleviating diabetes-related cognitive impairment, and promoting osteoblast differentiation; its target is DPP-4 (selective inhibition, non-covalent binding). It can also activate signaling pathways such as AMPK/SOX-9, PI3K/Akt/GSK-3β, PI3K/Akt/GLUT4, and AMPK/ACC-RUNX2, with lower selectivity for DPP-8 and DPP-9.

IC50 data: in vitro human recombinant DPP-4 IC50 1.3 nM, DPP-8 IC50 5.5 μM, DPP-9 IC50 19 μM; it can be used for model treatment. Common models include STZ + high-fat diet-induced diabetic rat model, db/db mouse T2DM model, high-fat diet-induced obese diabetic mouse model, and ZDF rat diabetic model, for evaluating glucose lowering, cognitive improvement, and other effects.

Common application concentrations: in cell culture, C-28/I2 human chondrocytes 30, 60 μM (24 h, no cytotoxicity; cell viability begins to be inhibited above 300 μM), 3T3-L1 insulin-resistant adipocytes 12.5, 25, 50, 100 μM (48 h), MC3T3-E1 osteoblasts 50 μM (14 days; cell viability decreases above 250 μM), and nM-level concentrations for DPP-4 inhibitory activity assays; in animal experiments, rats 40 mg/kg once weekly by gavage (for 3 months), mice 1-10 mg/kg, rats 3-10 mg/kg orally; clinically, T2DM patients take 5 mg or 10 mg orally once weekly; effects corresponding to effective treatment concentrations: clinically, 10 mg/week can reduce HbA?c by about 0.8% from baseline and lower fasting blood glucose; in animal experiments, 40 mg/kg/week can reduce fasting blood glucose in diabetic rats from 25.1±4.1 mmol/L to 16.8±3.2 mmol/L and improve spatial learning and memory; at the cellular level, 50, 100 μM can improve insulin resistance in adipocytes, 30-60 μM can inhibit inflammation and oxidative stress in chondrocytes, and 50 μM can promote osteoblast differentiation and mineralization.

References:

[1] Luo Z, Chen X, Wang G, Du Z, Ma X, Wang H, Yu G, Liu A, Li M, Peng W, Liu Y. Development of a validated HPLC method for the quantitative determination of trelagliptin succinate and its related substances in pharmaceutical dosage forms. Eur J Pharm Sci. 2018 Jan 1;111:458-464. doi: 10.1016/j.ejps.2017.10.028. Epub 2017 Oct 21. PMID: 29066384.

[2] Liu Z, Xu L, Xing M, Xu X, Wei J, Wang J, Kang W. Trelagliptin succinate: DPP-4 inhibitor to improve insulin resistance in adipocytes. Biomed Pharmacother. 2020 May;125:109952. doi: 10.1016/j.biopha.2020.109952. Epub 2020 Feb 6. PMID: 32036216.

[3] Shao H, Wu R, Cao L, Gu H, Chai F. Trelagliptin stimulates osteoblastic differentiation by increasing runt-related transcription factor 2 (RUNX2): a therapeutic implication in osteoporosis. Bioengineered. 2021 Dec;12(1):960-968. doi: 10.1080/21655979.2021.1900633. PMID: 33734011; PMCID: PMC8291811.

[4] Liu J, Zuo Q, Li Z, Chen J, Liu F. Trelagliptin ameliorates IL-1β-impaired chondrocyte function via the AMPK/SOX-9 pathway. Mol Immunol. 2021 Dec;140:70-76. doi: 10.1016/j.molimm.2021.09.009. Epub 2021 Oct 16. PMID: 34666245.

[5] Lei M, Guo X, Yao Y, Shu T, Ren Z, Yang X, Ouyang C, Chen Q, Liu C, Liu X. Trelagliptin relieved cognitive impairment of diabetes mellitus rats: Involvement of PI3K/Akt/GSK-3β and inflammation pathway. Exp Gerontol. 2023 Oct 15;182:112307. doi: 10.1016/j.exger.2023.112307. Epub 2023 Oct 7. PMID: 37804920.