Key result
Novel P2Y1 receptor antagonists potently reduce cerebral infarct size in rat stroke models.
Novel P2Y1 receptor antagonists compounds 19 and 36b show promising neuroprotective and infarct-reducing effects in preclinical models of ischemic stroke.
To develop effective agents for ischemic stroke, compounds 19 (IC 50 = 0.49 μM) and 36b (IC 50 = 0.50 μM), as analogues of our previously reported antiplatelet agent HNW001, were identified as potent P2Y 1 receptor antagonists, which were superior to HNW001 and BPTU (IC 50 = 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 ED 50 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.
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Zhang et al. (2025) studied Ischemic stroke. Compounds 19 and 36b vs. HNW001 and BPTU was evaluated on P2Y1 receptor antagonism (IC50) and reduction of infarction sizes (ED50). Compounds 19 and 36b acted as potent P2Y1 receptor antagonists (IC50 0.49 and 0.50 μM) and effectively reduced infarction sizes in a rat MCAO model (ED50 8.39 and 4.60 mg/kg).
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