Abstract

BI 1356 [proposed trade name ONDERO; (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] is a novel dipeptidyl peptidase (DPP)-4 inhibitor under clinical development for the treatment of type 2 diabetes. In this study, we investigated the potency, selectivity, mechanism, and duration of action of BI 1356 in vitro and in vivo and compared it with other DPP-4 inhibitors. BI 1356 inhibited DPP-4 activity in vitro with an IC₅₀ of approximately 1 nM, compared with sitagliptin (19 nM), alogliptin (24 nM), saxagliptin (50 nM), and vildagliptin (62 nM). BI 1356 was a competitive inhibitor, with a K_i of 1 nM. The calculated k_off rate for BI 1356 was 3.0 × 10^–5/s (versus 2.1 × 10^–4/s for vildagliptin). BI 1356 was ≥10,000-fold more selective for DPP-4 than DPP-8, DPP-9, amino-peptidases N and P, prolyloligopeptidase, trypsin, plasmin, and thrombin and was 90-fold more selective than for fibroblast activation protein in vitro. In HanWistar rats, the DPP-4 inhibition 24 h after administration of BI 1356 was more profound than with any of the other DPP-4 inhibitors. In C57BL/6J mice and Zucker fatty (fa/fa) rats, the duration of action on glucose tolerance decreased in the order BI 1356 > (sitagliptin/saxagliptin) > vildagliptin. These effects were mediated through control of glucagon-like peptide-1 and insulin. In conclusion, BI 1356 inhibited DPP-4 more effectively than vildagliptin, sitagliptin, saxagliptin, and alogliptin and has the potential to become the first truly once-a-day DPP-4 inhibitor for the treatment of type 2 diabetes.