Received for publication July 24, 2008.
Revised October 28, 2008.
Accepted for publication October 28, 2008.

Chronic Treatment with the Dipeptidyl Peptidase-4 Inhibitor (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) Increases Basal Glucagon-Like Peptide-1 and Improves Glycemic Control in Diabetic Rodent Models

Abstract

Antidiabetic effects of dipeptidyl peptidase (DPP)-4 inhibitors are exerted by potentiation of the biological activity of incretin hormones like glucagon-like peptide (GLP)-1. 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 competitive, selective, potent and long-acting DPP-4 inhibitor under clinical development for the treatment of type 2 diabetes. The effect of 1-2 months of chronic dosing of BI 1356 in two different animal models is investigated. The first is a primarily genetic model (Zucker Diabetic Fatty (ZDF) rats) and the second is a non-genetic model (mice with diabetes induced by a combination of high fat diet (HFD) and a low-dose streptozotocin (STZ)). BI 1356 was shown to lower HbA1c after multiple dosing in both models. The improvement of glycemic control achieved in disease models of different etiology suggests that BI 1356 would also be efficacious in treating a broad spectrum of type 2 diabetic patients. In addition, multiple dosing of BI 1356 leads to a sustained increase in basal levels of active GLP-1 in the systemic circulation with expected long-term benefits on pancreatic - and -cells. The effects on HbA1c, as well as, GLP-1 were superior to the short-acting DPP-4 inhibitor vildagliptin, demonstrating the potential of BI 1356 as a once-daily treatment for type 2 diabetes at low therapeutic doses.

Key words: BI 1356, Zucker Diabetic Fatty rats, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1, glycemic control, streptozotocin