Cinnamyl derivatives: synthesis and factor Xa (FXa) inhibitory activities.
To develop a potent and oral anticoagulant, a series of compounds with cinnamyl moiety was synthesized and their factor Xa (FXa) inhibitory activities were examined. As a result, some cinnamyl derivatives showed potent FXa inhibitory activities in vitro. Among them, compounds with substituent at the 3-position on the central benzene ring represented by (N-{4-[1-(acetimidoyl)piperidin-4-yloxy]-3-chlorophenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45b) and (N-{4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45j) exhibited potent FXa inhibitory activities with IC(50) values of less than 10 nM in vitro. These compounds also showed potent anticoagulant activities both in vitro and ex vivo. Furthermore, these compounds exhibited no lethal toxicity (30 mg/kg, i.v.).
Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co Ltd, Tokyo, Japan.
Tetsuji
T
Noguchi
Naoki
N
Tanaka
Toyoki
T
Nishimata
Riki
R
Goto
Miho
M
Hayakawa
Atsuhiro
A
Sugidachi
Taketoshi
T
Ogawa
Fumitoshi
F
Asai
Koichi
K
Fujimoto
D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects; D002934:Cinnamates / Q000138:chemical synthesis* / Q000494:pharmacology*; D006224:Cricetinae; D065427:Factor Xa Inhibitors; D006801:Humans; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D014361:Trypsin Inhibitors / Q000494:pharmacology
D002934:Cinnamates; D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D014361:Trypsin Inhibitors