New histamine H-3-receptor ligands of the proxifan series: Imoproxifan andother selective antagonists with high oral in vivo potency

Histamine Ha-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. Synt hesis of the novel compounds and X-ray crystallography of one highly potent oxime derivative, named imoproxifan (4-(3-(1H-imidazol-4-yl)propyloxy)phen ylethanone oxime), are described. Most of the title compounds possess high antagonist potency in histamine H-3-receptor assays in vitro as well as in vivo in mouse CNS following po administration. Structure-activity relations hips are discussed. Imoproxifan displays subnanomolar potency on a function al assay on synaptosomes of rat cerebral cortex (K-i = 0.26 nM). In vivo, i moproxifan increases the central N-tau-methylhistamine level with an ED50 o f 0.034 mg/kg po. A receptor profile on several functional in vitro assays was determined for imoproxifan, demonstrating high selectivity toward the h istamine H-3 receptor for this promising candidate for further development.