Design,synthesis and biological activity of YM-60828 derivatives: potent and orally-bioavailable factor Xa inhibitors based on naphthoanilide and naphthalensulfonanilide templates |
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Authors: | Hirayama Fukushi Koshio Hiroyuki Ishihara Tsukasa Watanuki Susumu Hachiya Shunichiro Kaizawa Hiroyuki Kuramochi Takahiro Katayama Naoko Kurihara Hiroyuki Taniuchi Yuta Sato Kazuo Sakai-Moritani Yumiko Kaku Seiji 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. hirayaf@yamanouchi.co.jp |
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Abstract: | Factor Xa (FXa) is a serine protease which plays a pivotal role in the coagulation cascade. The inhibition of FXa has received great interest as a potential target for the development of new antithrombotic drug. Herein we describe a series of novel 7-amidino-2-naphthoanilide and 7-amidino-2-naphthalensulfonanilide derivatives which are potent FXa inhibitors. These scaffolds are rigid and are allowed to adopt an L-shape conformation which was estimated as the active conformation based on a docking study of YM-60828 with FXa. Optimization of the side chain at the central aniline nitrogen of 7-amidino-2-naphthoanilide has led to several potent and orally active FXa inhibitors. 5h (YM-169964), the best compound of these series, showed potent FXa inhibitory activity (IC(50)=3.9nM) and effectively prolonged prothrombin time by 9.6-fold ex vivo at an oral dose of 3mg/kg in squirrel monkeys. |
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