C273 trihydrochloride is a potent, selective, oral bioavailable, and brain penetratn mitochondrial complex I (mtCI; NADH:ubiquinone oxidoreductase) modulator, protects against Aβ toxicity via modulation of mtCI.
C273 activates AMPK and coordinated antioxidant, autophagic, anti-inflammatory, and mitochondrial quality-control pathways in cultured cells and mouse brain.
C273 retains protection against Aβ-induced toxicity with minimal intrinsic cytotoxicity.
C273 protects MC65 Tet-Off cells from Aβ-induced toxicity with EC50 of 14.2 nM.
C273 inhibits mtCI activity with IC50 of 201.5 uM in isolated mouse brain mitochondria, with no detectable inhibition of complexes II, III, or IV.
C273 activates AMPK-dependent mitochondrial stress signaling and neuroprotective pathways, enhances oxidative stress resistance, restores redox balance, and promotes mitochondrial quality control.
C273 activates target engagement biomarkers in PBMCs and reduce Aβ and p-Tau in human LOAD organoids.