C458

C458 is a novel small-molecule partial mitochondrial complex I (mtCI) inhibitor developed through rational design and extensive structure-activity relationship studies, using CP2 as a tool compound. It weakly inhibits mtCI, which activates AMPK, triggering a neuroprotective stress response. This response enhances oxidative stress protection, promotes autophagy, and increases mitochondrial biogenesis and turnover, ultimately protecting against Aβ toxicity. C458 has demonstrated excellent bioavailability, blood-brain barrier penetrance, and a clean safety profile. Preclinical studies in APP/PS1 mice showed that chronic oral administration of C458 preserved cognition, improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis. It is being investigated as a disease-modifying strategy for Alzheimer's Disease.