Design, synthesis and evaluation of pyrimidine derivatives as sedative-hypnotic agents

Insomnia is a mental disorder in which drugs only alleviate the symptoms but also produce adverse effects. Therefore, developing innovative sedative-hypnotic agents is urgent. In this work, twenty-five novel heteroatomic compounds were designed, synthesized, and screened for their sedative activities, structurally featuring the fusion of pyrimidine and carbazole or benzothiazole. Most of the synthesized compounds showed distinct sedative activities in vivo. Among them, 4l displayed excellent sedative and hypnotic properties in the dose range of 0.1-2.5 mg/kg, and was superior to diazepam at 5 mg/kg. Mechanism studies showed 4l induced sedative-hypnotic effects via activating cAMP/PKA/CREB signaling pathway. Moreover, 4l possessed appropriate blood brain barrier permeability and excellent bioavailability (F: 74.5 ± 4.5 %). Thus, 4l was identified as the lead compound owing to its favorable potency and pharmacokinetic profiles, providing alternative for insomnia drugs development.