title: Design and synthesis of 3-pyridylacetamide derivatives as dipeptidyl peptidase IV (DPP-4) inhibitors targeting a bidentate interaction with Arg125.
abstract: We have previously discovered nicotinic acid derivative 1 as a structurally novel dipeptidyl peptidase IV (DPP-4) inhibitor. In this study, we obtained the X-ray co-crystal structure between nicotinic acid derivative 1 and DPP-4. From these X-ray co-crystallography results, to achieve more potent inhibitory activity, we targeted Arg125 as a potential amino acid residue because it was located near the pyridine core, and some known DPP-4 inhibitors were reported to interact with this residue. We hypothesized that the guanidino group of Arg125 could interact with two hydrogen-bond acceptors in a bidentate manner. Therefore, we designed a series of 3-pyridylacetamide derivatives possessing an additional hydrogen-bond acceptor that could have the desired bidentate interaction with Arg125. We discovered the dihydrochloride of 1-{[5-(aminomethyl)-2-methyl-4-(4-methylphenyl)-6-(2-methylpropyl)pyridin-3-yl]acetyl}-l-prolinamide (13j) to be a potent and selective DPP-4 inhibitor that could interact with the guanidino group of Arg125 in a unique bidentate manner.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-Chome, Yodogawa-ku, Osaka 532-8686, Japan. Miyamoto_Yasufumi@takeda.co.jp
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Banno
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Oi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Moritoh
authors.forename: Tomoko
authors.initials: T
authors.lastname: Asakawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Kataoka
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Koji
authors.initials: K
authors.lastname: Ikedo
authors.forename: Takuo
authors.initials: T
authors.lastname: Kosaka
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Tsubotani
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Tani
authors.forename: Miyuki
authors.initials: M
authors.lastname: Funami
authors.forename: Michiko
authors.initials: M
authors.lastname: Amano
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Kathleen
authors.initials: K
authors.lastname: Aertgeerts
authors.forename: Jason
authors.initials: J
authors.lastname: Yano
authors.forename: Hironobu
authors.initials: H
authors.lastname: Maezaki
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D001120:Arginine / Q000737:chemistry*; D018360:Crystallography, X-Ray; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: D000081:Acetamides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D001120:Arginine