title: Design, synthesis, and biological activity of novel factor Xa inhibitors: improving metabolic stability by S1 and S4 ligand modification.
abstract: Serine protease factor xa (fXa) inhibitor 1 showed good ex vivo anti-fXa activity upon oral administration in rats. However, it has been revealed that 1 had low metabolic stability against human liver microsomes. To improve the metabolic stability, we attempted to modify the S1 and S4 ligands of 1. These modifications resulted in compound 34b, which exhibited selective anti-fXa activity and excellent anti-coagulation activity.
authors.affiliation: Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd, Edogawa-ku, Japan. komor0ni@daiichipharm.co.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Komoriya
authors.forename: Shozo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Ken
authors.initials: K
authors.lastname: Osanai
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yoshino
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nagata
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Haginoya
authors.forename: Yumi
authors.initials: Y
authors.lastname: Nakamoto
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Mochizuki
authors.forename: Takayasu
authors.initials: T
authors.lastname: Nagahara
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimada
authors.forename: Kengo
authors.initials: K
authors.lastname: Watanabe
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Isobe
authors.forename: Taketoshi
authors.initials: T
authors.lastname: Furugoori
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000494:pharmacology*; D000990:Antithrombin III / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008862:Microsomes, Liver / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D008024:Ligands; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D000990:Antithrombin III