Spiro-Substituted Piperidines as Neurokinin Receptor Antagonists. I. Design and Synthesis of (±)-N-[2-(3,4-Dichlorophenyl)-4-(spiro[isobenzofuran-1(3H), 4'-piperidin]-1'-yl)butyl]-N-methylbenzamide, YM-35375,as a New Lead Compound for Novel Neurokinin Rec

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概要

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• Analysis of the structural requirements of compound 1 (SR48968), a potent NK_2 receptor antagonist, revealed that the 4-phenyl group of the piperidine is essential for binding with the NK_2 receptor and occupies an equatorial position. Energy calculation of a variety of substituted 4-phenyl piperidines revealed that spiro[isobenzofuran-1(3H), 4'-piperidine] possesses a conformationally restricted equatorial phenyl group. Our compound 12 (YM-35375) possessing this spiro-substituted piperidine bound to the NK_2 receptor with an IC_<50> value of 84nM and to NK_1 receptor with an IC_<50> value of 710nM. It showed more potent inhibitory activity (ID_<50> 41μg/kg (i.v.)) against [β-Ala^8]-NKA(4-10)-induced bronchoconstriction in guinea pigs than (±)-SR48968 (ID_<50> 68μg/kg (i.v.)). YM-35375 may be a new lead compound for novel NK_2 receptor antagonists or NK_1-NK_2 dual antagonists.

• 公益社団法人日本薬学会の論文
• 1998-02-15

著者

• 池田 潔

  School Of Pharmaceutical Sciences University Of Shizuoka

• 池田 潔

  Tanabe Seiyaku Co. Ltd. Saitama Jpn

• Fujii M

  Samsung Yokohama Res. Inst. Co. Ltd. Yokohama‐shi Jpn

• Fujii M

  Tokyo University Of Science:(present Office)utsunomiya University

• Fujii M

  Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn

• Takeuchi M

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Takeuchi Makoto

  Chemistry Research Laboratories Astellas Pharmaceutical Inc.

• TAKEUCHI Makoto

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• SHIBANUMA Tadao

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• ISOMURA Yasuo

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• Takeuchi M

  Chemistry Research Laboratories Astellas Pharmaceutical Inc.

• Isomura Y

  Yamanouchi Pharmaceutical Co. Ltd. Ibaraki Jpn

• Ikeda Kiyoshi

  Department Of Biochemistry Osaka University Of Pharmaceutical Sciences

• Fujii M

  Showa Univ. Tokyo Jpn

• FUJII Masahiro

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• KUBOTA Hirokazu

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• IKEDA Ken

  Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd.,

• Shibanuma Tadao

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co. Ltd.

• Shibanuma Tadao

  Institute For Drug Discovery Research Yamanouchi Pharmaceutical Co.

• Kubota H

  Chemistry Research Laboratories Astellas Pharmaceutical Inc.

• 池田 かおり

  Developmental Research Laboratories Shionogi & Co. Ltd.

• Ikeda Kaori

  Developmental Research Laboratories Shionogi & Co. Ltd.

• Kurihara H

  Chemistry Research Laboratories Astellas Pharmaceutical Inc.

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