Linagliptin (BI-1356)

BI1356 is a potent and competitive DPP-4 inhibitor, which exhibited DPP-4 inhibiting activity in several independent tests with IC50 values of 0.4, 0.5, 0.9, and 1.1nM.[1]
DPP-4 is an N-terminal dipeptidyl exopeptidase existing as a membrane-bound protein and also as a soluble protein in plasma. It plays a major role in the degradation of incretins such as GLP-1 which is of great importance in the process of glucose metabolism. Under physiological conditions, GLP-1 is truncated by DPP-4 rapidly, which is located on the capillary endothelium proximal to the L-cells where GLP-1 is secreted in the ileum. GLP-1 could sensitize β-cells to glucose stimulation,consequently increasing intracellular cAMP concentrations in β-cells and accelerating and augmenting insulin response to absorb glucose. By being measured at the substrate at the binding site, BI1356 inhibits the DPP-4 enzyme.[1]
DPP-4 was extracted from confluent Caco-2 cells to determine the inhibition activity of BI1356. Assays were performed by mixing the inhibitor solution with substrates and the Caco-2 cell extract, which illustrated BI1356 inhibited DPP-4 with IC 50 values of 0.4, 0.5, 0.9, and 1.1 nM. BI1356 also possesses a very significant selectivity for DPP-4 relative to other dipeptidyl peptidases aminopeptidases N and P, prolyloligopeptidase, and the proteases trypsin, plasmin, and thrombin.[1]
An in vivo evaluation showed that BI1356 dose-dependently inhibited the DPP-4 enzyme in plasma within 30 min of administration. Separate doses ranging from 1 to 10 mg/kg achieved significant inhibition activity of DPP-4, which also showed persistent DPP-4 inhibition activity. The ED50 value for inhibition of plasma DPP-4 activity was calculated to be 0.9 mg/kg 24 h post dose. In a clinical study,  BI1356 produced a remarkable, clinically meaningful and persistent improvement in glycaemic control, in accordance with enhanced parameters of β-cell function.  Patients treated with BI1356 were more likely to achieve a reduction in HbA1c of ≥ 0.5% comparing control.[1,2]
References:
1.Thomas L, Eckhardt M, Langkopf E, et al. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3, 7-dihydro-purine-2, 6-dione (BI 1356), a novel  xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors[J]. Journal of Pharmacology and Experimental Therapeutics, 2008, 325(1): 175-182.
2.Del Prato S, Barnett A H, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of β‐cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial[J]. Diabetes, Obesity and Metabolism, 2011, 13(3): 258-267.