Linagliptin (GSK2118436)

2 years -80 in solvent

Administered via p.o.

Linagliptin is currently in Phase IV clinical trials in Type 2 diabetic patients with and without chronic renal failure.

Linagliptin is dissolved in 0.1 N HCl and subsequently diluted with a 0.5% aqueous hydroxyethylcellulose solution (final HCl concentration 3 mM).

Linagliptin shows a potent inhibition effect against DPP-4 in vitro and a low affinity for hERG channel and M1 receptor (IC50 295 nM). [1] Linagliptin acts as a competitive inhibitor with a Ki of 1 nM, and also shows 10, 000-fold more selectivity for DPP-4 than DPP-8, DPP-9, amino-peptidases N and P, prolyloligopeptidase, trypsin, plasmin, and thrombin, and 90-fold more selectivity than, fibroblast activation protein in vitro. [2]

In Vitro DPP-4 Inhibition Assay, For determination of the in vitro potency of inhibitors, an extract from the human colon carcinoma cell line Caco-2 is used as source of the DPP-4 enzyme. Caco-2 cells are grown to confluency in cell culture flasks in EMEM medium supplemented with non-essential amino acids and containing 10% heat-inactivated fetal calf serum. Cells are washed with PBS and 4 mL lysis buffer (10 mM Tris-HCl, 150 mM NaCl, 0.04 U/mL aprotinin, 0.5% Nonidet P40, pH 8.0) are added per flask. After 5 minute incubation at room temperature with gentle agitation, cells are centrifuged at 4 C for 30 minutes and the supernatant is stored at -80C. Prior to use, the extract is diluted 1000-fold with assay buffer (100 mM Tris-HCl, 100 mM NaCl, pH 7.8). A 200 mM stock solution

Linagliptin (GSK2118436) is a highly potent, selective DPP-4 inhibitor with IC50 of 1 nM and exhibits a 10, 000-fold higher selectivity for DPP-4 than for other dipeptidyl peptidases such as DPP-2, DPP-8, and DPP-9. Linagliptin activates glomerular autophagy in a model of type 2 diabetes. DPP4 mediates ferroptosis in TP53-deficient CRC cells.