Structural Requirements for Potent Na/H Exchange Inhibitors Obtained from Quantitative Structure-Activity Relationships of Monocyclic and Bicyclic Aroylguanidines

概要

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The quantitative structure-activity relationship (QSAR) of N-(3-amino-6-chloro-5-ethylisopropylaminopyrazine-4-carbonyl)guanidine (EIPA) 1ac and its derivatives as Na/H exchange inhibitors was analyzed using the steric parameters and an indicator variable. The results indicated that bicyclic aroylguanidines might have Na/H exchange inhibitory activity. Therefore, various bicyclic aroylguanidines were synthesized and tested for Na/H exchange inhibitory activity. The QSAR study of the bicylic aroylguanidines showed that hydrophobic bicyclic rings seemed to be preferable for potent activity. The hydrophobicity of the aroyl ring moiety was thought to be paticularly important. Thus, the QSAR of EIPA and its derivatives was re-analyzed using hydrophobicity and steric parameters. The results indicated that high hydrophobicity of the pseudo-ring moiety and a substituent of appropriate length at the position corresponding to the 5-position of the naphthalene ring enhance the activity. As expected from the results, 5-bromo-2-naphthoylguanidine 3b and 5-methoxy-2-naphthoylguanidine 3c exhibited strong activity. These findings will be helpful to design new, potent Na/H exchange inhibitors.
公益社団法人日本薬学会の論文
1997-08-15