title: Synthesis and biological activity of novel 1,2-disubstituted benzene derivatives as factor Xa inhibitors.
abstract: Factor Xa (fXa) is a serine protease that plays a pivotal role in the coagulation cascade. High-throughput screening of the Yamanouchi compound library yielded lead compound 1 with the ability to inhibit fXa at micromolar concentrations. To improve its fXa inhibitory activity and its oral anticoagulant activity, the linker between benzamidine and the central benzene ring was modified and a carboxyl group was introduced at the central benzene ring. The resulting compounds 40b (YM-203552), 41a (YM-202054), and 41c (YM-203558) exhibited potent fXa inhibitory activity and oral anticoagulant activity. In particular, YM-203558 exhibited the most potent oral anticoagulant activity, prolonging PT more than 3-fold at 0.5 and 2.0 h. Additionally, these compounds showed a high degree of selectivity for other serine proteases.
authors.affiliation: 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: Ryouta
authors.initials: R
authors.lastname: Shiraki
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: Seiji
authors.initials: S
authors.lastname: Kaku
authors.forename: Naoko
authors.initials: N
authors.lastname: Katayama
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: D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D001555:Benzene Derivatives; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors