Indoline derivatives II: synthesis and factor Xa (FXa) inhibitory activities |
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Authors: | Noguchi Tetsuji Tanaka Naoki Nishimata Toyoki Goto Riki Hayakawa Miho Sugidachi Atsuhiro Ogawa Taketoshi Asai Fumitoshi Ozeki Tomoko Fujimoto Koichi |
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Institution: | Medicinal Chemistry Research Laboratories, Sankyo Co., Ltd., Tokyo, Japan. |
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Abstract: | 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, ({(RS)-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 11d ((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. |
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