Received for publication December 21, 2007.
Revised January 24, 2008.
Accepted for publication January 24, 2008.

BI 1356 (proposed trade name ONDERO), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other DPP-4 inhibitors

Abstract

BI 1356 (proposed tradename ONDERO) 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 approx 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 3.0x10^-5 s^-1 (versus 2.1x10^-4 s^-1 for vildagliptin). BI 1356 was 10,000-fold more selective for DPP 4 than DPP-8, DPP-9, aminopeptidases N and P, prolyloligopeptidase, trypsin, plasmin and thrombin, and was 90 fold more selective than for fibroblast activation protein (FAP) 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 C57BI/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.

Key words: ONDERO, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1, glycemic control, oral pharmacological agents, type 2 diabetes