Design, synthesis, and biological activity of novel factor Xa inhibitors: improving metabolic stability by S1 and S4 ligand modification.
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.
Komoriya
Satoshi
S
Tokyo R&D Center, Daiichi Pharmaceutical Co. Ltd, Edogawa-ku, Japan. komor0ni@daiichipharm.co.jp
Kobayashi
Shozo
S
Osanai
Ken
K
Yoshino
Toshiharu
T
Nagata
Tsutomu
T
Haginoya
Noriyasu
N
Nakamoto
Yumi
Y
Mochizuki
Akiyoshi
A
Nagahara
Takayasu
T
Suzuki
Makoto
M
Shimada
Takashi
T
Watanabe
Kengo
K
Isobe
Yumiko
Y
Furugoori
Taketoshi
T
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
D000925:Anticoagulants; D008024:Ligands; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D000990:Antithrombin III