title: Orally active factor Xa inhibitor: synthesis and biological activity of masked amidines as prodrugs of novel 1,4-diazepane derivatives.
abstract: Factor Xa (fXa) is a serine protease, which plays a pivotal role in the coagulation cascade. To improve the oral anticoagulant activity of fXa inhibitors containing a 1,4-diazepane moiety as the P4 part, a prodrug strategy was examined. Among the compounds evaluated in this study, amidoxime prodrugs bearing an ester moiety, such as compounds 21 and 30, showed effective oral anticoagulant activity in mice.
authors.affiliation: Chemistry Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. koshio@yamanouchi.co.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koshio
authors.forename: Fukushi
authors.initials: F
authors.lastname: Hirayama
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Ishihara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kaizawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Shigenaga
authors.forename: Yuta
authors.initials: Y
authors.lastname: Taniuchi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sato
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Moritani
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Iwatsuki
authors.forename: Toshio
authors.initials: T
authors.lastname: Uemura
authors.forename: Seiji
authors.initials: S
authors.lastname: Kaku
authors.forename: Tomihisa
authors.initials: T
authors.lastname: Kawasaki
authors.forename: Yuzo
authors.initials: Y
authors.lastname: Matsumoto
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000990:Antithrombin III / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001780:Blood Coagulation Tests; D005260:Female; D006801:Humans; D051379:Mice; D011247:Pregnancy; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000578:Amidines; D000925:Anticoagulants; D001372:Aza Compounds; D011355:Prodrugs; D000990:Antithrombin III