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

Sasse, A; Sadek, B; Ligneau, X; Elz, S; Pertz, HH; Luger, P; ... Stark, H; + view all (2000) New histamine H-3-receptor ligands of the proxifan series: Imoproxifan and other selective antagonists with high oral in vivo potency. Journal of Medicinal Chemistry , 43 (17) 3335 - 3343.

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Abstract

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. 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 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 H-3 receptor for this promising candidate for further development

Type:Article
Title:New histamine H-3-receptor ligands of the proxifan series: Imoproxifan and other selective antagonists with high oral in vivo potency
Additional information:Journal Article AUG 24 349BJ Stark H Free Univ Berlin, Inst Pharm, Konigin Luisse Str 2-4, D-14195 Berlin, Germany J MED CHEM
Keywords:Administration, antagonist, ANTAGONISTS, As, ASSAY, Brain, Cerebral, cerebral cortex, CEREBRAL-CORTEX, CN, CNS, CONSTANTS STATISTICAL EVALUATION, cortex, development, functional, groups, H-3, H-3 receptor, H-3 RECEPTOR HETEROGENEITY, H3, HIGH-AFFINITY, HIGHLY POTENT, Histamine, I-125 IODOPROXYFAN, in vitro, in vivo, In-vitro, IN-VITRO PHARMACOLOGY, in-vivo, INCREASES, inhibition, LEVEL, LIGAND, ligands, MED, modulation, mouse, novel, Oral, Other, POTENT, rat, Receptor, release, SELECTIVITY, SERIES, Structure, Structure Activity Relationship, structure-activity, Structure-Activity Relationship, synthesis, VERONGAMINE, X-ray
UCL classification:UCL > School of BEAMS > Faculty of Maths and Physical Sciences > Chemistry

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