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 receptor antagonists

Article abstract of DOI:10.1248/cpb.46.351

Analysis of the structural requirements of compound 1 (SR48968), a potent NK₂ receptor antagonist, revealed that the 4-phenyl group of the piperidine is essential for binding with the NK₂ 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 NK₂ receptor with an IC₅₀ value of 84nM and to the NK₁ receptor with an IC₅₀ value of 710nM. It showed more potent inhibitory activity (ID₅₀ 41μg/kg (i.v.)) against [β-Ala⁸]-NKA(4-10)-induced bronchoconstriction in guinea pigs than (±)-SR48968 (ID₅₀ 68μg/kg (i.v.)). YM-35375 may be a new lead compound for novel NK₂ receptor antagonists or NK₁-NK₂ dual antagonists.

Full text of DOI:10.1248/cpb.46.351

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