[2-(ω-Phenylalkyl)phenoxy]alkylamines III : Synthesis and Selective Serotonin-2 Receptor Binding (2)

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概要

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• A series of [2-(2-phenylethyl)phenoxy]ethylpyrrolidine derivatives were synthesized, and their affinity for serotonin-2 (5-HT_2) and dopamine-2 (D_2) receptors was examiend. Among them, compound 17,(2R, 4R)-4-hydroxy-2-[2-[2-[2-(3-methoxyphenyl)ethyl]phenoxy]ehtyl]-1-methylpyrrolidine hydrochloride. showed high 5-HT_2 receptor affinity in vitro. This compound was a more potent inhibitor of ex vivo 5-HT-induced platelet aggregation than compound 3,which was previously shown to be more potent than ketanserin (1) and sarpogrelate (2a). However, compound 17 produced gastric irritaiton in rats. Therefore, we carried out a further derivatization of 17,and compound 45 (R-102444), a lauryl ester prodrug of compound 17,was found to be a promising candidate as an antithrombotic agent. Oral administration of R-102444 produced a marked inhibition of 5-HT-induced ex vivo platelet aggregation, and R-102444 did not cause any gastric irritation. The antiaggregatory effects of R-102444 were more potent than those of sarpogrelate (2a) and its active metabolite, M-1 (2b). In addition, R-102444 exhibited more potent antithrombotic effects than sarpogrelate in a rat photochemically-induced thrombosis model.

• 公益社団法人日本薬学会の論文
• 2000-11-01

著者

• Tanaka N

  Department Of Pharmacology School Of Pharmaceutical Sciences Mukogawa Women's University

• Tanaka Naoko

  武庫川女子大学 薬学部薬理学

• Tanaka Naoki

  Medical ProteoScope Co., Ltd.

• Ito R

  Medicinal Chemistry Research Laboratories Sankyo Co. Ltd.

• Ito Rie

  Clinical Pharmacy College Of Pharmacy Nihon University

• 中西 務

  Faculty Of Pharmaceutical Sciences Setsunan University

• Ito Rie

  Medicinal Chemistry Research Laboratories Sankyo Co. Ltd.

• Tanaka N

  School Of Pharmaceutical Sciences Mukogawa Women S University

• Ogawa T

  R & D Division Daiichi Sankyo Co. Ltd.

• GOTO Riki

  Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd.

• HAYAKAWA Miho

  Medicinal Chemistry Research Laboratories II, Daiichi Sankyo Co., Ltd.

• FUJIMOTO Koichi

  Medicinal Chemistry Research Laboratories I, Daiichi Sankyo Co., Ltd.

• SUGIDACHI Atsuhiro

  Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd.

• OGAWA Taketoshi

  Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd.

• ASAI Fumitoshi

  Pharmacology and Molecular Biology Research Laboratories, Sankyo Co., Ltd.

• Goto R

  R & D Division Daiichi Sankyo Co. Ltd.

• Hayakawa Miho

  R & D Division Daiichi Sankyo Co. Ltd.

• Asai Fumitoshi

  R & D Division Daiichi Sankyo Co. Ltd.

• Fujimoto K

  R & D Division Daiichi Sankyo Co. Ltd.

• Sugidachi Atsuhiro

  R & D Division Daiichi Sankyo Co. Ltd.

• Nishimata Toyoki

  R & D Division Daiichi Sankyo Co. Ltd.

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