Synthesis of nonimidazole H receptor antagonists containing oxazole moiety and their antiseizure activity.

Epilepsy is one of the most common neurological disorders and presents various obstacles to the fulfilling lives of people. Histamine H receptors (HR) antagonists are becoming a promising therapeutic approach for epilepsy. In this paper, a series of novel nonimidazole HR antagonists have been designed, and synthesized. cAMP-response element (CRE) luciferase screening assay was used to evaluated their HR antagonistic activities. And their antiseizure activities were evaluated using the maximal electroshock seizure (MES)-induced seizure model. Among them, compounds 6a (IC = 0.30 μM), 6c (IC = 0.37 μM), 6f (IC = 0.30 μM), 6m (IC = 0.31 μM), and 6n (IC = 0.35 μM) displayed the most potent HR antagonistic activities and exhibited high selectivity, without significant antagonistic activity against HR, HR, and HR. In the MES model, compounds 6a, 6c, 6f, 6m, and 6n showed varying degrees of protection for the electro-stimulated mice. Compound 6n was considered to be the most promising one, with an ED values of 20.2 mg/kg. The antiseizure activity of 6a and 6n was also established in the PTZ-induced seizure model, with the ability to reduce the total movement distance significantly induced by PTZ. What's more, the protection of 6n against the MES-induced seizures was abrogated when mice were co-treated with RAMH, a CNS-penetrant HR agonist, which suggested that the potential therapeutic effect of 6n was through HR. Safety evaluation suggested that 6n has relatively lower cytotoxicity and neurotoxicity, although it shows hERG cardiotoxicity. Overall, this study provides a new source for antiseizure drug research whereby inhibiting HR is expected to yield new antiseizure drugs.