Furoxan analogues of the histamine H 3-receptor antagonist imoproxifan and related furazan derivatives

• Published in: Bioorganic & medicinal chemistry Vol. 13; no. 15; pp. 4750 - 4759
• Main Authors: Tosco, Paolo, Bertinaria, Massimo, Stilo, Antonella Di, Cena, Clara, Sorba, Giovanni, Fruttero, Roberta, Gasco, Alberto
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.08.2005
• Subjects: Furazans; Furoxans; H 3-antagonists; Histamine; Histamine; Furazans; Furoxans; H 3-antagonists
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2005.05.004

Constrained analogues of imoproxifan containing furazan ( n = 0) and furoxan ( n = 1) systems were synthesised and evaluated in vitro as H 3-antagonists. Synthesis and pharmacological characterisation of a series of compounds in which the oxime substructure present in imoproxifan was constrained in the pentatomic NO-donor furoxan ring, as well as their structurally related furazan analogues devoid of NO-donating properties, are described. The whole series of products displayed reversible histamine H 3-antagonistic activity on guinea-pig ileum. 4-(4-(3-(1 H-Imidazol-4-yl)propoxy)phenyl)furoxan-3-carbonitrile 16 was also able to induce partial relaxation when added to the bath after electrical contraction of the guinea-pig ileum during the study of its H 3-antagonistic properties. This phenomenon seems to be dependent on NO-mediated sGC activation. The lipophilic–hydrophilic balance of all the products was investigated.