title: Orally active zwitterionic factor Xa inhibitors with long duration of action.
abstract: We have optimized 2-aminomethylphenylamine derivative as a factor Xa inhibitor. Several polar functional groups were introduced in the central phenyl ring, and we focused on zwitter ionic compound showing continuous inhibitory activity in oral administration test. In vitro and oral activities were improved by optimization of S1 and S4 ligands. Incorporating the interaction with S1-β pocket enhanced in vitro factor Xa inhibitory activity to less than 1 nM. Many zwitter ionic compounds showed long duration of action and potent inhibitory activity and high AUC values in oral administration tests to monkeys.
authors: Research and Development Division, Daiichi Sankyo Co., Ltd, 1-16-13 Kita-Kasai, Tokyo 134-8630, Japan. mochizuki.akiyoshi.yk@daiichisankyo.co.jp
authors: Akiyoshi
authors: A
authors: Mochizuki
authors: Tsutomu
authors: T
authors: Nagata
authors: Hideyuki
authors: H
authors: Kanno
authors: Daisuke
authors: D
authors: Takano
authors: Masamichi
authors: M
authors: Kishida
authors: Makoto
authors: M
authors: Suzuki
authors: Toshiharu
authors: T
authors: Ohta
mesh_terms: D000284:Administration, Oral; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D001665:Binding Sites; D003198:Computer Simulation; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D000882:Haplorhini; D007477:Ions / Q000737:chemistry; D017434:Protein Structure, Tertiary; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D013329:Structure-Activity Relationship
chemical_list: C558704:2-aminomethylphenylamine; D000814:Aniline Compounds; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007477:Ions; D015842:Serine Proteinase Inhibitors; D015951:Factor Xa