Synthesis and biological activity of novel 1,4-diazepane derivatives as factor Xa inhibitor with potent anticoagulant and antithrombotic activity.
Factor Xa (fXa) is a serine protease involved in the coagulation cascade, which has received great interest as a potential target for the development of new antithrombotic drugs. Herein we report a novel series of fXa inhibitors in which the 1,4-diazepane moiety was designed to interact with the S4 aryl-binding domain of the fXa active site. Compound 13 (YM-96765) showed potent fXa inhibitory activity (IC(50) = 6.8 nM) and effective antithrombotic activity without prolonging bleeding time.
Koshio
Hiroyuki
H
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. koshio@yamanouchi.co.jp
Hirayama
Fukushi
F
Ishihara
Tsukasa
T
Taniuchi
Yuta
Y
Sato
Kazuo
K
Sakai-Moritani
Yumiko
Y
Kaku
Seiji
S
Kawasaki
Tomihisa
T
Matsumoto
Yuzo
Y
Sakamoto
Shuichi
S
Tsukamoto
Shin-ichi
S
D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004285:Dogs; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D001372:Aza Compounds; D015842:Serine Proteinase Inhibitors