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

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.