New Histamine H3-Receptor Ligands of the Proxifan Series: Imoproxifan and
Other Selective Antagonists with High Oral in Vivo Potency
Web Release Date: August 5,
New Histamine H3-Receptor Ligands of the Proxifan Series: Imoproxifan and
Other Selective Antagonists with High Oral in Vivo Potency
Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany; Laboratoire Bioprojet, 30 rue des Francs-Bourgeois, 75003 Paris, France; Institut für Chemie/Kristallographie, Freie Universität Berlin, Takustrasse 6, 14195 Berlin, Germany; Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London WC1H 0AJ, U.K.; and Unité de Neurobiologie et Pharmacologie Moléculaire (U. 109), Centre Paul Broca de l'INSERM, 2ter rue d'Alésia, 75014 Paris, France
Received April 26, 2000
Abstract:
Histamine H3-receptor antagonists of the proxifan series are described. The novel compounds
possess a 4-(3-(phenoxy)propyl)-1H-imidazole structure and various functional groups, e.g., an
oxime moiety, on the phenyl ring. Synthesis of the novel compounds and X-ray crystallography
of one highly potent oxime derivative, named imoproxifan (4-(3-(1H-imidazol-4-yl)propyloxy)phenylethanone oxime), are described. Most of the title compounds possess high antagonist
potency in histamine H3-receptor assays in vitro as well as in vivo in mouse CNS following po
administration. Structure-activity relationships are discussed. Imoproxifan displays subnanomolar potency on a functional assay on synaptosomes of rat cerebral cortex (Ki = 0.26 nM).
In vivo, imoproxifan increases the central N
-methylhistamine level with an ED50 of 0.034 mg/kg po. A receptor profile on several functional in vitro assays was determined for imoproxifan,
demonstrating high selectivity toward the histamine H3 receptor for this promising candidate
for further development.