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

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...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2012-10, Vol.20 (19), p.5864-5883
Main Authors: Ikuma, Yohei, Hochigai, Hitoshi, Kimura, Hidenori, Nunami, Noriko, Kobayashi, Tomonori, Uchiyama, Katsuya, Furuta, Yudai, Sakai, Mutsuko, Horiguchi, Masakuni, Masui, Yumi, Okazaki, Kazuhiko, Sato, Yasuhiro, Nakahira, Hiroyuki
Format: Article
Language:English
Subjects:
3H-Imidazo[4,5-c]quinolin-4(5H)-one
Biological and medical sciences
chemistry
Diabetes Mellitus, Type 2 - drug therapy
Diabetes Mellitus, Type 2 - enzymology
Dipeptidyl Peptidase 4 - metabolism
Dipeptidyl peptidase IV
Dipeptidyl-Peptidase IV Inhibitors - chemistry
Dipeptidyl-Peptidase IV Inhibitors - pharmacology
Humans
Imidazoles - chemistry
Imidazoles - pharmacology
Indexing in process
Lys554
Medical sciences
Molecular Docking Simulation
noninsulin-dependent diabetes mellitus
palladium
Pharmacology. Drug treatments
Quinolines - chemistry
Quinolines - pharmacology
risk
skeleton
Type 2 diabetes
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2012.07.046