Design, synthesis, anti-acute ischemic stroke (AIS) effect of receptor-interacting protein kinase 1 (RIPK1) inhibitors containing quinazoline structure.

Receptor-interacting protein kinase 1 (RIPK1) plays a pivotal role in necroptosis, a regulated form of cell death that contributes to neuronal damage and inflammation. RIPK1 inhibitors have emerged as promising therapeutic agents in the treatment of acute ischemic stroke. In this study, a series of novel RIPK1 inhibitors were designed and synthesized based on a new scaffold containing quinazoline and benzotriazole moieties. Their potent inhibitory activity, selectivity for RIPK1 over RIPK3 and anti-necroptotic activity at the cellular level were then evaluated. Notably, compound 9b emerged as an optimal candidate, offering substantial neuroprotection by inhibiting the phosphorylation of RIPK1, RIPK3, and mixed lineage kinase domain-like pseudokinase (MLKL) within the necroptosis pathway. In vivo evaluations in a rat middle cerebral artery occlusion (MCAO) model highlighted compound 9b's neuroprotective effect. Initial assessments of the compound revealed its low toxicity, stable metabolic profile, and favorable permeability across the blood-brain barrier, highlighting its promising potential as a therapeutic agent for AIS.