Indoline Derivatives II : Synthesis and Factor Xa (FXa) Inhibitory Activities
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概要
- 論文の詳細を見る
Factor Xa (FXa) is well known to play a pivotal role in blood coagulation, so FXa inhibitor is a promising drug candidate for prophylaxis and treatment of thromboembolic diseases. In the course of our research, we have found that (R)-5-[1-(acetimidoyl) piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)-1-(ethanesulfonyl)indoline ((R)-1) showed potent FXa inhibitory activity in vitro. However, single oral administation (RS)-1 showed high toxicity in mice. Among newly synthesized compounds, ({(R5)-5-[1-(acetimidoyl) piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)indolin-1-yl}sulfonyl) acetic acid ((RS)-11d) showed more potent FXa inhibitory activity and higher safety than (RS)-1. The R-isoform of compound lid ((R)-11d) exhibited potent in vitro anticoagulant activity in human and hamster plasma. Orally administered (R)-11d also showed dose-dependent potent anticoagulant activity in hamsters, marmosets and cynomolgus monkeys. Compound (R)-11d with potent anticoagulant activity and high safety is therefore favorable as a novel oral FXa inhibitor.
- 公益社団法人日本薬学会の論文
- 2007-03-01
著者
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Tanaka N
Department Of Pharmacology School Of Pharmaceutical Sciences Mukogawa Women's University
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Tanaka Naoko
武庫川女子大学 薬学部薬理学
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Tanaka Naoki
Medical ProteoScope Co., Ltd.
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中西 務
Faculty Of Pharmaceutical Sciences Setsunan University
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Tanaka N
School Of Pharmaceutical Sciences Mukogawa Women S University
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Ogawa T
R & D Division Daiichi Sankyo Co. Ltd.
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NOGUCHI Tetsuji
Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd.
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NISHIMATA Toyoki
Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd.
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GOTO Riki
Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd.
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HAYAKAWA Miho
Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd.
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FUJIMOTO Koichi
Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd.
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SUGIDACHI Atsuhiro
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd.
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OGAWA Taketoshi
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd.
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ASAI Fumitoshi
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd.
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OZEKI Tomoko
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Co., Ltd.
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Goto R
R & D Division Daiichi Sankyo Co. Ltd.
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Ozeki Tomoko
Drug Metabolism And Pharmacokinetics Research Laboratories Sankyo Co. Ltd.
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Hayakawa Miho
R & D Division Daiichi Sankyo Co. Ltd.
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Asai Fumitoshi
R & D Division Daiichi Sankyo Co. Ltd.
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Fujimoto K
R & D Division Daiichi Sankyo Co. Ltd.
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Noguchi Tetsuji
R & D Division Daiichi Sankyo Co. Ltd.
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Sugidachi Atsuhiro
R & D Division Daiichi Sankyo Co. Ltd.
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Nishimata Toyoki
R & D Division Daiichi Sankyo Co. Ltd.
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