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<p>This study aimed to develop novel non-imidazole histamine H<sub>3</sub> receptor (H<sub>3</sub>R) antagonists as potential antiseizure agents. We designed and synthesized a series of 2-aryloxazole derivatives (<b>4a-4t</b>) by relocating a phenyl group from the piperidine side chain to the oxazole core of a previous the lead compound (<b>5&#xa0;g</b>), aiming to optimize lipophilicity and receptor binding. Among the synthesized compounds, <b>4f</b> exhibited the most potent H<sub>3</sub>R antagonistic activity (IC<sub>50</sub> = 0.056 µM), superior to lead compound <b>5&#xa0;g</b> and the reference drug Pitolisant (PIT). Compound <b>4f</b> also demonstrated high selectivity over other histamine receptor subtypes (H<sub>1</sub>R, H<sub>2</sub>R, and H<sub>4</sub>R). In vivo, <b>4f</b> showed significant and sustained antiseizure efficacy in the maximal electroshock (MES) model in mice (ED<sub>50</sub> = 17.36&#xa0;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&#xa0;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 <b>4f</b> as a potent, selective, and brain-penetrable H<sub>3</sub>R antagonist with robust antiseizure activity and a favorable preclinical profile, supporting its further development as a novel antiseizure agent.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月14日

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  • Ying Zheng,
  • Guowen He,
  • Yingna Zhu,
  • Hao Qu,
  • Jieya Shang,
  • Jianglong Wu,
  • Zhaozhe Wang,
  • Xianqing Deng

摘要

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.