Synthesis and structure-activity relationships of novel selective factor Xa inhibitors with a tetrahydroisoquinoline ring |
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Authors: | Ueno Hiroshi Yokota Katsuyuki Hoshi Jun-Ichi Yasue Katsutaka Hayashi Mikio Hase Yasunori Uchida Itsuo Aisaka Kazuo Katoh Susumu Cho Hidetsura |
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Institution: | Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1, Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan. |
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Abstract: | A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkeys, showed a dose-dependent antithrombotic effect at 0.1, 0.3, and 1 mg kg(-1) h(-1) in a rat model of venous thrombosis, and significantly reduced the size of brain infarction in a middle cerebral artery occlusion model at a dose of 0.1 mg kg(-1) h(-1). These results suggest that compound 2 (JTV-803) is likely to be useful as both a venous and arterial antithrombotic agent. |
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