Synthesis and biological activity of novel 1,2-disubstituted benzene derivatives as factor Xa inhibitors.
Factor Xa (fXa) is a serine protease that plays a pivotal role in the coagulation cascade. High-throughput screening of the Yamanouchi compound library yielded lead compound 1 with the ability to inhibit fXa at micromolar concentrations. To improve its fXa inhibitory activity and its oral anticoagulant activity, the linker between benzamidine and the central benzene ring was modified and a carboxyl group was introduced at the central benzene ring. The resulting compounds 40b (YM-203552), 41a (YM-202054), and 41c (YM-203558) exhibited potent fXa inhibitory activity and oral anticoagulant activity. In particular, YM-203558 exhibited the most potent oral anticoagulant activity, prolonging PT more than 3-fold at 0.5 and 2.0 h. Additionally, these compounds showed a high degree of selectivity for other serine proteases.
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
Shiraki
Ryouta
R
Shigenaga
Takeshi
T
Taniuchi
Yuta
Y
Sato
Kazuo
K
Moritani
Yumiko
Y
Iwatsuki
Yoshiyuki
Y
Kaku
Seiji
S
Katayama
Naoko
N
Kawasaki
Tomihisa
T
Matsumoto
Yuzo
Y
Sakamoto
Shuichi
S
Tsukamoto
Shin-ichi
S
D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016339:Spectrometry, Mass, Fast Atom Bombardment
D001555:Benzene Derivatives; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors