Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors.

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Ikuma Y, Hochigai H, Kimura H, Nunami N, Kobayashi T, Uchiyama K, Furuta Y, Sakai M, Horiguchi M, Masui Y, Okazaki K, Sato Y, Nakahira H

Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors.

Bioorg Med Chem. 2012 Oct 1;20(19):5864-83. doi: 10.1016/j.bmc.2012.07.046. Epub 2012 Aug 5.

PubMed ID
22938786 [ View in PubMed
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Abstract

In recent years, dipeptidyl peptidase IV inhibitors have been noted as valuable agents for treatment of type 2 diabetes. Herein, we report the discovery of a novel potent DPP-4 inhibitor with 3H-imidazo[4,5-c]quinolin-4(5H)-one as skeleton. After efficient optimization of the lead compound 2a at the 7- and 8-positions using a docking study, we found 28 as a novel DPP-4 inhibitor with excellent selectivity against various DPP-4 homologues. Compound 28 showed strong DPP-4 inhibitory activity compared to marketed DPP-4 inhibitors. We also found that a carboxyl group at the 7-position could interact with the residue of Lys554 to form a salt bridge. Additionally, introduction of a carboxyl group to 7-position led to both activity enhancement and reduced risk for hERG channel inhibition and induced phospholipidosis. In our synthesis of compounds with 7-carboxyl group, we achieved efficient regioselective synthesis using bulky ester in the intramolecular palladium coupling reaction.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AlogliptinDipeptidyl peptidase 4IC 50 (nM)4N/AN/ADetails
LinagliptinDipeptidyl peptidase 4IC 50 (nM)1N/AN/ADetails
SaxagliptinDipeptidyl peptidase 4IC 50 (nM)3.37N/AN/ADetails
SitagliptinDipeptidyl peptidase 4IC 50 (nM)18N/AN/ADetails
VildagliptinDipeptidyl peptidase 4Ki (nM)3N/AN/ADetails