Spiro-Substituted Piperidines as Neurokinin Receptor Antagonists. III. Synthesis of (±)-N-[2-(3,4-Dichlorophenyl)-4-(spiro-substituted piperidin-1'-yl)butyl]-N-methylbenzamides and Evaluation of NK_1-NK_2 Dual Antagonistic Activities

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To discover a novel NK_1-NK_2 dual antagonist, we have synthesized a series of spiro-substituted piperidines utilizing YM-35375 as a lead compound, and evaluated affinities for NK_1 and NK_2 receptors. In the N-methylbenzamide moiety, introduction of methoxy groups increased affinity for the NK_1 receptor without a significant loss of affinity for the NK_2 receptor. We also found that a conformation in which the phenyl groups of the N-methylbenzamide and 3,4-dichlorophenyl moieties are close to each other through a cis-amide bond, may be favorable for showing high affinity for the NK_1 receptor and that a hydrogen bond-accepting group in the spiro-substituted piperidine moiety may be crucial for exhibiting high affinity for the NK_2 receptor. Among the compounds prepared, YM-44778 (31) showed high and well-balanced affinity for NK_1 and NK_2 receptors (IC_<50> values of 18 and 16 nM, respectively). This compound also exhibited potent antagonistic activities against both NK_1 and NK_2 receptors (IC_<50> values of 82 and 62 nM, respectively) in isolated tissues.
公益社団法人日本薬学会の論文
1998-10-15