Unsymmetrically substituted guanidines as potent histamine H3-receptor antagonists

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Abstract

Unsymmetrically trisubstituted and disubstituted guanidine derivatives of (1H-imidazol-4-yl)alkyl amines were synthesized and investigated for histamine H3-receptor activity. Electron-withdrawing substitution of the guanidino group resulted in antagonists with a potential prodrug character. The H3-receptor selective N1-cyclohexylmethyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidine possesses a -log Ki of 9.1.

Di- and trisubstituted guanidino derivatives of 4-(imidazoly)alkylamines are described as highly potent and selective histamine H3-receptor antagonists. The procedure of preparation with versatile synthons to result in differently substituted guanidines is given. N1-Cyclohexylmethyl-N2-[3-(1H-imidazol-4-yl)propyl]guanidine shows a Ki of 7.4x10−10M at H3-receptors and low activity at other histamine receptor sybtypes.

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