Progress in the proxifan class: heterocyclic congeners as novel potent and selective histamine H3-receptor antagonists

Sven Graßmann, Bassem Sadek, Xavier Ligneau, Sigurd Elz, C. Robin Ganellin, Jean Michel Arrang, Jean Charles Schwartz, Holger Stark, Walter Schunack

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)


Histamine H3 receptors are critically involved in the pathophysiology of several disorders of the central nervous system (CNS). Among other families of H3-receptor ligands, the proxifan class has recently been described to contain numerous potent histamine H3-receptor antagonists, e.g. ciproxifan or imoproxifan. In the present study, we report on the design of novel heterocyclic proxifan analogues and their antagonist potencies at histamine H3 receptors. The new compounds were tested for in vitro and in vivo H3-receptor antagonist potencies in different species as well as for H3-receptor selectivity vs. H1 and H2 receptors. In vitro, all compounds investigated proved to be potent H3-receptor antagonists in the rat as well as in the guinea-pig. In addition, they showed good to high oral CNS potency in vivo in mice. Especially, oxadiazole derivatives 24-26 displayed nanomolar antagonist activity in vitro and high potency in vivo (ED50=0.47-0.57 mg/kg). The results show that the additional heteroaromatic moieties might act as bioisosteres of the ketone or oxime moieties of ciproxifan or imoproxifan, respectively, and might cause divergent pharmacokinetic properties. Thus, these novel H3-receptor antagonists are interesting leads for further development.

Original languageEnglish
Pages (from-to)367-378
Number of pages12
JournalEuropean Journal of Pharmaceutical Sciences
Issue number4
Publication statusPublished - 2002
Externally publishedYes


  • Antagonist
  • Ciproxifan
  • H receptor
  • Histamine
  • Imoproxifan
  • Proxifan

ASJC Scopus subject areas

  • Pharmaceutical Science


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