Abstract
Antidiabetic effects of dipeptidyl peptidase-4 (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 to 2 months of chronic dosing of BI 1356 in two different animal models was investigated. The first is a primarily genetic model (Zucker diabetic fatty rats), and the second is a nongenetic model (mice with diabetes induced by a combination of high-fat diet and low-dose streptozotocin). 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 α- and β-cells. The effects on HbA1c and 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.
Footnotes
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Parts of this work were previously presented at the following conferences: Thomas L and Mark M (2008) BI 1356 (proposed trade name ONDERO), a novel xanthine-based DPP-4 inhibitor, improves glycaemic control after multiple dosing in various diabetic animal models. In 3rd International Conference on Dipeptidyl Peptidases and Related Proteins; 2008 Apr 23–25; Antwerp, Belgium. Organizing Committee of De Meester I, Scharpé S, and Haemers A, Antwerp, Belgium; and Thomas L, Tadayyon M, and Mark M (2008) BI 1356 (proposed trade name ONDERO), a novel xanthine-based DPP-4 inhibitor, increases basal GLP-1 and improves glycemic control in diabetic animals. In Proceedings of the American Diabetes Association 68th Scientific Sessions; 2008 June 6–10; San Francisco, CA. American Diabetes Association, San Francisco, CA.
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The chronic study in male ZDF rats was performed under contract by Rheoscience A/S (Roedovre, Denmark) with Niels Vrang and Mads Tang-Christensen as project managers and Kirsten Lykkegaard as study director.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.143966.
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ABBREVIATIONS: GLP, glucagon-like peptide; GIP, glucose-dependent insulinotropic polypeptide; DPP-4, dipeptidyl peptidase-4; BI 1356, (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; HFD, high-fat diet; STZ, streptozotocin; ZDF, Zucker diabetic fatty; NVP-DPP728, 1-[2-[(5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-(S)-pyrrolidinecarbonitrile; OGTT, oral glucose tolerance test; ANOVA, analysis of variance; AUC, area under the curve.
- Received July 23, 2008.
- Accepted October 28, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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Chronic Treatment with the Dipeptidyl Peptidase-4 Inhibitor BI 1356 [(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] Increases Basal Glucagon-Like Peptide-1 and Improves Glycemic Control in Diabetic Rodent Models
