title: New histamine H(3)-receptor ligands of the proxifan series: imoproxifan and other selective antagonists with high oral in vivo potency.
abstract: Histamine H(3)-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 H(3)-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 (K(i) = 0.26 nM). In vivo, imoproxifan increases the central N(tau)-methylhistamine level with an ED(50) 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 H(3) receptor for this promising candidate for further development.
authors.affiliation: Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sasse
authors.forename: B
authors.initials: B
authors.lastname: Sadek
authors.forename: X
authors.initials: X
authors.lastname: Ligneau
authors.forename: S
authors.initials: S
authors.lastname: Elz
authors.forename: H H
authors.initials: HH
authors.lastname: Pertz
authors.forename: P
authors.initials: P
authors.lastname: Luger
authors.forename: C R
authors.initials: CR
authors.lastname: Ganellin
authors.forename: J M
authors.initials: JM
authors.lastname: Arrang
authors.forename: J C
authors.initials: JC
authors.lastname: Schwartz
authors.forename: W
authors.initials: W
authors.lastname: Schunack
authors.forename: H
authors.initials: H
authors.lastname: Stark
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000502:physiology / Q000648:ultrastructure; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008761:Methylhistamines / Q000378:metabolism; D051379:Mice; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011969:Receptors, Histamine H1 / Q000187:drug effects; D011970:Receptors, Histamine H2 / Q000187:drug effects; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000502:physiology
chemical_list: D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D010091:Oximes; D011969:Receptors, Histamine H1; D011970:Receptors, Histamine H2; D018100:Receptors, Histamine H3; C413352:imoproxifan; C031205:3-methylhistamine