Design,synthesis and biological activity of YM-60828 derivatives. Part 2: potent and orally-bioavailable factor Xa inhibitors based on benzothiadiazine-4-one template |
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Authors: | Hirayama Fukushi Koshio Hiroyuki Katayama Naoko Ishihara Tsukasa Kaizawa Hiroyuki Taniuchi Yuta Sato Kazuo Sakai-Moritani Yumiko Kaku Seiji Kurihara Hiroyuki 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.ac.jp |
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Abstract: | Compound YM-60828 was previously characterized in our laboratory as a potent, selective and orally-bioavailable Factor Xa (FXa) inhibitor. The L-shape conformation of this compound in the active site of FXa was recognized as an important factor in displaying its FXa inhibitory activity. This led to the exploration of conformationally restricted cyclic scaffolds bearing a similar active conformation. The current study investigated a novel series of benzothiadiazine-4-one based compounds as FXa inhibitors. Structure-activity relationship (SAR) investigations revealed some potent FXa inhibitors that were selected for further in vitro and ex vivo anticoagulant studies. Among them, compound 6j (YM-169920) was proved to be most effective anticoagulant in this series. The synthesis and SAR in addition to docking studies of this class of inhibitors are described. |
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