title: 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.
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 alpha- and beta-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.
authors.affiliation: Boehringer Ingelheim Pharma GmbH and Co. KG, Department of Metabolic Diseases Research, Birkendorfer Strasse 65, D-88397 Biberach an der Riss, Germany. leo.thomas@boehringer-ingelheim.com
authors.forename: Leo
authors.initials: L
authors.lastname: Thomas
authors.forename: Moh
authors.initials: M
authors.lastname: Tadayyon
authors.forename: Michael
authors.initials: M
authors.lastname: Mark
mesh_terms: D000818:Animals; D003920:Diabetes Mellitus / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D038321:Glycemic Index / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000069476:Linagliptin; D008297:Male; D051379:Mice; D011687:Purines / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D051381:Rats; D011924:Rats, Zucker; D014407:Tumor Cells, Cultured
chemical_list: D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D052216:Glucagon-Like Peptide 1