1404554-18-2Relevant academic research and scientific papers
Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors
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
, p. 5864 - 5883,20 (2012/10/30)
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.
