Spiro-Substituted Piperidines as Neurokinin Receptor Antagonists. II. Syntheses and NK_2 Receptor-Antagonistic Activities of N-[2-Aryl-4-(spiro-substituted piperidin-1'-yl)butyl]carboxamides

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In the course of our research on spiro-compounds as neurokinin receptor antagonists, N-[2-aryl-4-(spiro-substituted piperidin-1'-yl)butyl]carboxamides were designed, based on YM-35375 (3) as a lead compound, and evaluated for NK_2 receptor-antagonistic activities. Some derivatives inhibited the binding of radio-labeled neurokinin A to the NK_2 receptor with IC_<50> values at the level of 10^<-9>M. Among these compounds, (±)-1'-[4-(N-benzoyl-N-methylamino)-3-(3,4-dichlorophenyl)butyl]spiro[benzo[c]thiophene-1(3H), 4'-piperidine] 2-oxide (58,YM-38336) showed 10 times more potent NK_2 receptor binding affinity than compound 3 (IC_<50> values of 8.9 and 84nM, respectively). It showed more potent inhibitory activity (ID_<50> 20μg/kg (i.v.)) against [β-Ala^8]-NKA(4-10)-induced bronchoconstriction in guinea pigs than compound 3 (ID_<50> 41μg/kg (i.v.)). This compound was also effective intraduodenally in the same model, exhibiting an ID_<50> value of 0.41μg/kg.
公益社団法人日本薬学会の論文
1998-02-15