Novel Phenoxyalkylamine Derivatives. III. : Quantitative Structure-Activity Relationships of Ca^<2+>-Antagonistic α-Alkyla-α-[(phenoxypropylamino)propyl]-3,4,5-trimethoxy-benzeneacetonitrile Derivatives

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The effects of structural modifications of α-alkyl-α-[(phenoxypropylamino)propyl-3,4,5-trimethoxybenzeneacetonitrile derivatives on their Ca^<2+> -antagonistic activity were analyzed qunatitatively by means of the Hansch-Fujita method. The effect of the alkyl substituent at the α-quaternary carbon atom was rationalized by a parabolic function of either steric paramater MR or ΔB_5,where the optimal value is MR=1.83 or ΔB_5=3.04. For substituents on the benzene ring (B ring) at the phenoxy moiety, an electron-releasing substituent with about π=0 seemed to be most favorable to the activity. The correlations with the local steric and hydrophobic parameters, ΔB^<para>_5 and π_<para>, of the para substiuent of the B ring showed that a substituent with small width and high hydrophobicity is favorable in enhancing activity, leading to the conclusion that hydrogen is the most preferable para substituent. The most effective compound (24) examined in this study has an m-OMe group on the B ring and an iso-Pr group at the quaternary carbon atom. This observation was in agreement with the present analyses.
社団法人日本薬学会の論文
1988-02-25