Synthesis and antiseizure effect evaluation of nonimidazole histamine H receptor antagonists containing the oxazole moiety.

The use of histamine H receptor (H R) antagonists is becoming a promising therapeutic approach for epilepsy. In this paper, a series of novel nonimidazole H R antagonists was synthesized and screened as antiepileptic drugs. All of these prepared antagonists displayed micromolar or submicromolar H R antagonistic activities in the cAMP response element luciferase screening assay. Compounds 5a (IC  = 0.11 μM), 5b (IC  = 0.56 μM), and 5f (IC  = 0.78 μM) displayed the most potent H R antagonistic activities, with considerable potency when compared with pitolisant (IC  = 0.51 μM). In the maximal electroshock (MES)-induced seizure model, compounds 5c, 5e, and 5g showed obvious protection for the electrostimulated mice, and the protection of 5g against the MES-induced seizures was fully abrogated when mice were cotreated with R-(α)-methyl-histamine, a central nervous system-penetrant H R agonist, suggesting that the potential therapeutic effect of 5g was observed to work through H R. These results indicate that the attempt to find a new antiepileptic drug among H R antagonists is practicable, but it is necessary to consider the log P of the molecules to ensure penetration of the blood-brain barrier.