Design, Synthesis, and Biological Evaluation of 4-(Difluoromethyl)-1H-imidazole-5-carboxylic Acids/4-(3-Cyanophenoxy)pyrimidine-5-carboxylic Acids as P2Y1 Receptor Antagonists for Ischemic Stroke Treatment

To develop effective agents for ischemic stroke, compounds 19 (IC₅₀ = 0.49 μM) and 36b (IC₅₀ = 0.50 μM), as analogues of our previously reported antiplatelet agent HNW001, were identified as potent P2Y₁ receptor antagonists, which were superior to HNW001 and BPTU (IC₅₀ = 4.07 and 2.50 μM, respectively). Notably, these two compounds showed remarkable neuroprotective potency against oxidative stress by upregulating nuclear Nrf2 protein levels in vitro. Additionally, compounds 19 and 36b demonstrated favorable blood-brain barrier penetration potential in rats, and the rat MCAO model showed that they could effectively reduce infarction sizes with ED₅₀ values of 8.39 and 4.60 mg/kg, respectively. Meanwhile, they could remarkably ameliorate neurobehavioral function, brain water content, oxidative parameters, and hippocampal tissue damage following MCAO. Thus, compounds 19 and 36b were promising lead compounds for developing effective agents to treat ischemic stroke.