Design, Synthesis, and Pharmacological Evaluation of Sulfur‐Containing Pitolisant Analogs as Potent H ₃ R Antagonists for Epilepsy Therapy

ABSTRACT

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 H ₃ receptor (H ₃ R) 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 H ₃ R 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 H ₃ R antagonism with IC ₅₀ values of 0.18 µM and 0.036 µM, respectively, with the latter more active than PIT (IC ₅₀  = 0.1 µM). In the maximal electroshock (MES) model, 3f exhibited superior antiseizure activity (ED ₅₀  = 14.0 mg/kg) compared to PIT (ED ₅₀  = 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 IC ₅₀ of 1.83 µM compared to PIT (IC ₅₀  = 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 H ₃ R 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.