Progress in the proxifan class: heterocyclic congeners as novel potent and selective histamine H(3)-receptor antagonists.

Histamine H(3) receptors are critically involved in the pathophysiology of several disorders of the central nervous system (CNS). Among other families of H(3)-receptor ligands, the proxifan class has recently been described to contain numerous potent histamine H(3)-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 H(3) receptors. The new compounds were tested for in vitro and in vivo H(3)-receptor antagonist potencies in different species as well as for H(3)-receptor selectivity vs. H(1) and H(2) receptors. In vitro, all compounds investigated proved to be potent H(3)-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 (ED(50)=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 H(3)-receptor antagonists are interesting leads for further development.