title: Spiro-substituted piperidines as neurokinin receptor antagonists. II. Syntheses and NK2 receptor-antagonistic activities of N-[2-aryl-4-(spiro-substituted piperidin-1'-yl)butyl]carboxamides.
abstract: 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 NK2 receptor-antagonistic activities. Some derivatives inhibited the binding of radio-labeled neurokinin A to the NK2 receptor with IC50 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 NK2 receptor binding affinity than compound 3 (IC50 values of 8.9 and 84 nM, respectively). It showed more potent inhibitory activity (ID50 20 micrograms/kg (i.v.)) against [beta-Ala8]-NKA(4-10)-induced bronchoconstriction in guinea pigs than compound 3 (ID50 41 micrograms/kg (i.v.)). This compound was also effective intraduodenally in the same model, exhibiting an ID50 value of 0.41 microgram/kg.
authors.affiliation: Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kubota
authors.forename: A
authors.initials: A
authors.lastname: Kakefuda
authors.forename: H
authors.initials: H
authors.lastname: Nagaoka
authors.forename: O
authors.initials: O
authors.lastname: Yamamoto
authors.forename: K
authors.initials: K
authors.lastname: Ikeda
authors.forename: M
authors.initials: M
authors.lastname: Takeuchi
authors.forename: T
authors.initials: T
authors.lastname: Shibanuma
authors.forename: Y
authors.initials: Y
authors.lastname: Isomura
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D006224:Cricetinae; D006168:Guinea Pigs; D007700:Kinetics; D019906:Nuclear Magnetic Resonance, Biomolecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D001743:Urinary Bladder / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D000577:Amides; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D013141:Spiro Compounds; C111211:YM 35375