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J Med Chem. 1998 Oct 8;41(21):4171-6.

4-Alkynylphenyl imidazolylpropyl ethers as selective histamine H3-receptor antagonists with high oral central nervous system activity.

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Institut für Pharmazie I, Freie Universität Berlin, Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany.


In search for potent and therapeutically useful H3-receptor antagonists, we prepared novel 4-alkynylphenyl ether derivatives of 3-(1H-imidazol-4-yl)propanol in a convenient synthetic route. All compounds were tested for in vitro and in vivo H3-receptor antagonist activity as well as for H3-receptor selectivity versus H1- and H2-receptors. The presented 4-alkynylphenyl ethers are highly potent and selective H3 antagonists showing oral activity and improved brain penetration. Particularly 4-ethynylphenyl 3-(1H-imidazol-4-yl)propyl ether (14a) displays striking in vitro and in vivo activity with a -log Ki value of 8.6 and an ED50 value of 0.12 mg/kg. At present 14a is the most potent H3-receptor antagonist in vivo and may therefore be a potential drug for the therapy of H3-receptor-dependent diseases of the central nervous system (CNS).

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