title: Discovery of piperazinylimidazo[1,2-a]pyridines as novel S4 binding elements for orally active factor Xa inhibitors.
abstract: We have recently reported the discovery of orally active sulfonylalkylamide Factor Xa (FXa) inhibitors, as typified by compound 1 (FXa IC(50)=0.061 microM). Since the pyridylpiperidine moiety was not investigated in our previous study, we conducted detailed structure-activity relationship studies on this S4 binding element. This investigation led to the discovery of piperazinylimidazo[1,2-a]pyridine 2b as a novel and potent FXa inhibitor (FXa IC(50)=0.021 microM). Further modification resulted in the discovery of 2-hydroxymethylimidazo[1,2-a]pyridine 2e (FXa IC(50)=0.0090 microM), which was found to be a selective and orally bioavailable FXa inhibitor with reduced CYP3A4 inhibition.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd, 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan. Imaeda_Yasuhiro@takeda.co.jp
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Imaeda
authors.forename: Tetsuji
authors.initials: T
authors.lastname: Kawamoto
authors.forename: Mamoru
authors.initials: M
authors.lastname: Tobisu
authors.forename: Noriko
authors.initials: N
authors.lastname: Konishi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Hiroe
authors.forename: Masaki
authors.initials: M
authors.lastname: Kawamura
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Keiji
authors.initials: K
authors.lastname: Kubo
mesh_terms: D000284:Administration, Oral; D001682:Biological Availability; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D011725:Pyridines; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human