4-Alkynylphenyl imidazolylpropyl ethers as selective histamine H3-receptor antagonists with high oral central nervous system activity.
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).
Institut für Pharmazie I, Freie Universität Berlin, Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany.
M
M
Krause
X
X
Ligneau
H
H
Stark
M
M
Garbarg
J C
JC
Schwartz
W
W
Schunack
D000284:Administration, Oral; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004987:Ethers / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011969:Receptors, Histamine H1 / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
C115074:4-ethynylphenyl 3-(1H-imidazol-4-yl)propyl ether; D004987:Ethers; D006633:Histamine Antagonists; D007093:Imidazoles; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3