Author/Authors :
Hiroyuki Koshio، نويسنده , , Fukushi Hirayama، نويسنده , , Tsukasa Ishihara، نويسنده , , Ryouta Shiraki، نويسنده , , Takeshi Shigenaga، نويسنده , , Yuta Taniuchi، نويسنده , , Kazuo Sato، نويسنده , , Yumiko Moritani، نويسنده , , Yoshiyuki Iwatsuki، نويسنده , , Seiji Kaku، نويسنده , , Naoko Katayama، نويسنده , , Tomihisa Kawasaki، نويسنده , , Yuzo Matsumoto، نويسنده , , Shuichi Sakamoto، نويسنده , , Shin-ichi Tsukamoto، نويسنده ,
Abstract :
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.
