Document Report Card

ID: ALA1132948

Journal: J Med Chem

Title: New histamine H(3)-receptor ligands of the proxifan series: imoproxifan and other selective antagonists with high oral in vivo potency.

Authors: Sasse A, Sadek B, Ligneau X, Elz S, Pertz HH, Luger P, Ganellin CR, Arrang JM, Schwartz JC, Schunack W, Stark H.

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.

CiteXplore: 10966752

DOI: 10.1021/jm000971p