title: Design, synthesis and SAR of novel ethylenediamine and phenylenediamine derivatives as factor Xa inhibitors.
abstract: We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30 h which showed both good in vitro activity (fXa IC(50) = 2.2 nM, PTCT2 = 3.9 μM) and in vivo antithrombotic efficacy.
authors.affiliation: R&D Division, Daiichi Sankyo Co, Ltd, 1-16-13, Kita-Kasai, Edogawa-ku, Tokyo 134-8630, Japan. yoshikawa.kenji.t6@daiichisankyo.co.jp
authors.forename: Kenji
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yoshino
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yokomizo
authors.forename: Kouichi
authors.initials: K
authors.lastname: Uoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Naito
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Kawakami
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Mochizuki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nagata
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kanno
authors.forename: Makoto
authors.initials: M
authors.lastname: Takemura
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Ohta
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D065427:Factor Xa Inhibitors; D008958:Models, Molecular; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors