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 (K
d,RIPK1 = 8.6 nM, K
d,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.
Systemic inflammatory response syndrome (SIRS), characterized
by
severe systemic inflammation, represents a major cause of health loss,
potentially leading to multiple organ failure, shock, and death. Exploring
potent RIPK1 inhibitors is an effective therapeutic strategy for SIRS.
Recently, we described thio-benzoxazepinones as novel RIPK1 inhibitors
and confirmed their anti-inflammatory activity. Herein, we further
synthesized novel thio-benzoxazepinones by introducing substitutions
on the benzene ring by an alkynyl bridge in order to extend the chemical
space from the RIPK1 allosteric to ATP binding pockets. The in vitro
cell and kinase assays found that compounds 2 and 29 showed highly potent activity against necroptosis (EC50 = 3.7 and 3.2 nM) and high RIPK1 inhibitory activity (K
d = 9.7 and 70 nM). Prominently, these two analogues
possessed better in vivo anti-inflammatory effects than the clinical
candidate GSK′772 and effectively blocked hypothermia and deaths
in a TNFα-induced SIRS model.
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