title: Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors.
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.
authors.affiliation: Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, 3-1-98 Kasugade Naka, Konohana-ku, Osaka 554-0022, Japan. yohei-ikuma@ds-pharma.co.jp
authors.forename: Yohei
authors.initials: Y
authors.lastname: Ikuma
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hochigai
authors.forename: Hidenori
authors.initials: H
authors.lastname: Kimura
authors.forename: Noriko
authors.initials: N
authors.lastname: Nunami
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Katsuya
authors.initials: K
authors.lastname: Uchiyama
authors.forename: Yudai
authors.initials: Y
authors.lastname: Furuta
authors.forename: Mutsuko
authors.initials: M
authors.lastname: Sakai
authors.forename: Masakuni
authors.initials: M
authors.lastname: Horiguchi
authors.forename: Yumi
authors.initials: Y
authors.lastname: Masui
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Okazaki
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Sato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakahira
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D011804:Quinolines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007093:Imidazoles; D011804:Quinolines; D018819:Dipeptidyl Peptidase 4