Design, Synthesis, and Biological Evaluation of 4-(Difluoromethyl)-1<i>H</i>-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 <b>19</b> (IC₅₀ = 0.49 μM) and <b>36b</b> (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 <b>19</b> and <b>36b</b> 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 <b>19</b> and <b>36b</b> were promising lead compounds for developing effective agents to treat ischemic stroke.