Design, synthesis, and biological activity of non-basic compounds as factor Xa inhibitors: SAR study of S1 and aryl binding sites.
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.
Komoriya
Satoshi
S
Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd, 16-13 Kita-Kasai 1-Chome, Edogawa-ku, Tokyo 134-8630, Japan. komor0ni@daiichipharm.co.jp
Haginoya
Noriyasu
N
Kobayashi
Shozo
S
Nagata
Tsutomu
T
Mochizuki
Akiyoshi
A
Suzuki
Masanori
M
Yoshino
Toshiharu
T
Horino
Haruhiko
H
Nagahara
Takayasu
T
Suzuki
Makoto
M
Isobe
Yumiko
Y
Furugoori
Taketoshi
T
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
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors