Abstract
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 IC50 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 Ki of 1 nM. The calculated koff rate for BI 1356 was 3.0 × 10–5/s (versus 2.1 × 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.
Footnotes
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Parts of this work were previously published as follows: Mark M, Himmelsbach F, Tadayyon M, Thomas L, Eckhardt M, and Langkopf E (2006) BI 1356, a novel potent and selective xanthine-based DPP-IV inhibitor, exhibits a unique profile. 19th World Diabetes Congress; 2006 Dec 3–7; Cape Town, South Africa. International Diabetes Federation, Brussels, Belgium; Thomas L, Himmelsbach F, Eckhardt M, Langkopf E, and Mark M (2007) BI 1356, a novel and selective xanthine-based DPP-4 inhibitor, exhibits a superior profile when compared to other DPP-4 inhibitors. 43rd Annual Meeting of the European Association for the Study of Diabetes. 2007 Sept 18–21; Amsterdam, The Netherlands. European Association for the Study of Diabetes, Dusseldorf, Germany.
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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.107.135723.
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ABBREVIATIONS: GLP, glucagon-like peptide; GIP, glucose-dependent insulinotropic peptide; DPP, dipeptidyl peptidase; 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; FAP, fibroblast activation protein; OGTT, oral glucose tolerance test; NVP-DPP728, 1-[2-[(5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-(S)-pyrrolidinecarbonitrile; AUC, area under the curve.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received December 21, 2007.
- Accepted January 24, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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