Design, synthesis and pharmacological evaluation of novel 2-aryloxazole-based H₃ receptor antagonists as potent,...

This study aimed to develop novel non-imidazole histamine H₃ receptor (H₃R) antagonists as potential antiseizure agents. We designed and synthesized a series of 2-aryloxazole derivatives (4a-4t) by relocating a phenyl group from the piperidine side chain to the oxazole core of a previous the lead compound (5 g), aiming to optimize lipophilicity and receptor binding. Among the synthesized compounds, 4f exhibited the most potent H₃R antagonistic activity (IC₅₀ = 0.056 µM), superior to lead compound 5 g and the reference drug Pitolisant (PIT). Compound 4f also demonstrated high selectivity over other histamine receptor subtypes (H₁R, H₂R, and H₄R). In vivo, 4f showed significant and sustained antiseizure efficacy in the maximal electroshock (MES) model in mice (ED₅₀ = 17.36 mg/kg) and potently suppressed seizures in a zebrafish pentylenetetrazol (PTZ) model. Pharmacokinetic studies revealed favorable oral bioavailability (81.12%) and effective brain penetration (90 min brain-to-plasma (B/P) ratio = 4.15) with progressive accumulation. Preliminary safety profiling indicated minimal neurotoxicity at therapeutic doses and a lower hERG channel inhibition risk compared to PIT. These results identify 4f as a potent, selective, and brain-penetrable H₃R antagonist with robust antiseizure activity and a favorable preclinical profile, supporting its further development as a novel antiseizure agent.