Design, Synthesis, and Pharmacological Evaluation of Sulfur-Containing Pitolisant Analogs as Potent H₃R Antagonists...

Although multiple antiseizure drugs (ASDs) are clinically accessible, epilepsy remains a debilitating neurological disorder with a high unmet need for more effective and better-tolerated therapies. Antagonism of the histamine H₃ receptor (H₃R) represents a promising alternative strategy, exemplified by the clinically approved inverse agonist/antagonist pitolisant (PIT) for narcolepsy. Herein, we designed a novel series of non-imidazole H₃R antagonists by introducing a sulfur atom into the PIT scaffold to modulate lipophilicity, flexibility, and target binding. The synthesis and pharmacological evaluation of 12 target compounds (3a-3h, 5a-5d) are reported. Compounds 3e and 3f showed potent H₃R antagonism with IC₅₀ values of 0.18 µM and 0.036 µM, respectively, with the latter more active than PIT (IC₅₀ = 0.1 µM). In the maximal electroshock (MES) model, 3f exhibited superior antiseizure activity (ED₅₀ = 14.0 mg/kg) compared to PIT (ED₅₀ = 16.3 mg/kg). What's more, compounds 3e and 3f showed significant seizure protection in a zebrafish pentylenetetrazol (PTZ) model, and favorable cytotoxicity and neurotoxicity profiles in cell and animal experiments. Compound 3f exhibits low hERG toxicity risk with an IC₅₀ of 1.83 µM compared to PIT (IC₅₀ = 1.51 µM), and excellent blood-brain barrier penetration with a brain-to-plasma ratio of 4.56. Molecular docking studies revealed stable interactions with key H₃R residues, including ASP114, VAL95, and PHE189. Collectively, these results indicate that 3f shows considerable promise as a lead candidate in the search for new antiepileptic drugs.