Synthesis and biological activity of novel 1,2-disubstituted benzene derivatives as factor Xa inhibitors |
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Authors: | Koshio Hiroyuki Hirayama Fukushi Ishihara Tsukasa Shiraki Ryouta Shigenaga Takeshi Taniuchi Yuta Sato Kazuo Moritani Yumiko Iwatsuki Yoshiyuki Kaku Seiji Katayama Naoko Kawasaki Tomihisa Matsumoto Yuzo Sakamoto Shuichi Tsukamoto Shin-ichi |
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Institution: | Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd, 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. koshio@yamanouchi.co.jp |
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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. |
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