Design, synthesis, and biological evaluation of novel brain-penetrant PARP7 inhibitors for the treatment of ischemic stroke.

Stroke remains a leading cause of mortality and neurological disability, highlighting the need for new therapeutic strategies. Recent studies have indicated that PARP7 is a novel target for stroke treatment. Herein, we report a series of small-molecule PARP7 inhibitors. Among these compounds, B-6 exhibited potent inhibitory activity on PARP7 (IC50 = 22.8 nM) and efficient blood-brain barrier (BBB) penetration (B/P = 63.7%). In vivo,B-6 demonstrated efficacy across multiple stroke models, significantly reducing cerebral infarct volume in the rat tMCAO model, and in both the rat tMCAO and mouse dMCAO models, suppressing acute inflammatory cytokine production and promoting sustained neurological and sensorimotor recovery over 21 days. Notably, B-6 retained neuroprotective efficacy when treatment was delayed for up to 12 h after ischemic onset. Cellular studies demonstrated that B-6-mediated PARP7 inhibition was accompanied by reduced neuroinflammation and astrocyte activation, attenuated autophagy-related alterations, and preserved synaptic marker expression. In summary, we have identified a brain-penetrable PARP7 inhibitor, B-6, and utilized it as a tool to further demonstrate that PARP7 could be a potential therapeutic target for stroke.