title: Design, synthesis, and biological activity of non-basic compounds as factor Xa inhibitors: SAR study of S1 and aryl binding sites.
abstract: Compound 7 was identified as the active metabolite of 6 by HPLC and mass spectral analysis. Modification of lead compound 7 by transformation of its N-oxide 6-6 biaryl ring system and fused aromatics produced a series of non-basic fXa inhibitors with excellent potency in anti-fXa and anticoagulant assays. The optimized compounds 73b and 75b showed sub to one digit micromolar anticoagulant activity (PTCT2). Particularly, anti-fXa activity was detected in plasma of rats orally administered with 1mg/kg of compound 75b.
authors.affiliation: Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd, 16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. komor0ni@daiichipharm.co.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Komoriya
authors.forename: Noriyasu
authors.initials: N
authors.lastname: Haginoya
authors.forename: Shozo
authors.initials: S
authors.lastname: Kobayashi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nagata
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Mochizuki
authors.forename: Masanori
authors.initials: M
authors.lastname: Suzuki
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Yoshino
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Horino
authors.forename: Takayasu
authors.initials: T
authors.lastname: Nagahara
authors.forename: Makoto
authors.initials: M
authors.lastname: Suzuki
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; D001665:Binding Sites; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006801:Humans; D007408:Intestinal Absorption; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors