Discovery of a Trifluoromethoxy Cyclopentanone Benzothiazole Receptor-Interacting Protein Kinase 1 Inhibitor as the Treatment for Alzheimer’s Disease

Receptor-interacting protein kinase 1 (RIPK1) contributes
to a
broad set of inflammations and necroptosis in human diseases, which
also plays an important role in the pathogenesis of Alzheimer’s
disease (AD). The inhibition of RIPK1 could be a novel strategy to
improve cognitive function. SZM679, a highly specific
RIPK1 inhibitor (Kd,RIPK1 = 8.6 nM, Kd,RIPK3 > 5000 nM), was developed by our
group
with superior high antinecroptotic activity (EC50 = 2 nM),
and investigated to completely reverse the tumor necrosis factor-induced
systemic inflammatory response syndrome. In a streptozocin-induced
AD-like mouse model, behavioral tests showed that SZM679 apparently ameliorated learning and memory dysfunction. Nissl staining
revealed that SZM679 improved neuronal loss. Moreover,
the Tau hyperphosphorylation, neuroinflammation, and the RIPK1 phosphorylation
level in the hippocampus and cortex were significantly decreased in
the SZM679-treated group. Collectively, SZM679 represents
a promising lead structure for the discovery of novel RIPK1 inhibitory
anti-AD agents.