(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), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors.
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 IC(50) 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 x 10(-5)/s (versus 2.1 x 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.
Thomas
Leo
L
Boehringer Ingelheim Pharma GmbH and Co. KG, Department of Metabolic Diseases Research, Birkendorfer Strasse 65, D-88397 Biberach, Germany. leo.thomas@boehringer-ingelheim.com
Eckhardt
Matthias
M
Langkopf
Elke
E
Tadayyon
Moh
M
Himmelsbach
Frank
F
Mark
Michael
M
D000818:Animals; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors; D018938:Caco-2 Cells; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010450:Endopeptidases; D018093:Gelatinases; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D020128:Inhibitory Concentration 50; D000069476:Linagliptin; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; D011687:Purines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D012697:Serine Endopeptidases; D014970:Xanthines; D000099167:Fibroblast Activation Protein Alpha
D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D010450:Endopeptidases; D018093:Gelatinases; D007004:Hypoglycemic Agents; D000069476:Linagliptin; D008565:Membrane Proteins; D011480:Protease Inhibitors; D011687:Purines; D011799:Quinazolines; D012697:Serine Endopeptidases; D014970:Xanthines; D000099167:Fibroblast Activation Protein Alpha; C042807:DPP4 protein, human