Drug Development

Area of Science:

• Neuroscience
• Biochemistry
• Pharmacology

Background:

• Alzheimer's Disease (AD) urgently needs disease-modifying strategies beyond amyloid reduction.
• Mitochondrial complex I (mtCI) is identified as a druggable target for AD.
• Previous work showed tool compound CP2 binds and weakly inhibits mtCI.

Purpose of the Study:

• Develop novel, selective, and safe partial mtCI inhibitors for AD.
• Evaluate preclinical candidates C458 and C273 for efficacy and safety.
• Investigate the neuroprotective mechanisms of mtCI inhibition in AD models.

Main Methods:

• Rational drug design and structure-activity relationship studies based on CP2.
• In vitro assays for target engagement, selectivity, efficacy, and safety.
• In vivo studies using APP/PS1 mice and C57BL/6 mice.

Main Results:

• Compounds C458 and C273 weakly inhibit mtCI, activating AMPK and a neuroprotective stress response.
• This response enhances antioxidant defenses, autophagy, and mitochondrial biogenesis, protecting against Aβ toxicity.
• C458 and C273 demonstrated good bioavailability, blood-brain barrier penetration, and a clean safety profile. Chronic C458 treatment in APP/PS1 mice preserved cognition and improved AD pathology markers.

Conclusions:

• Weak mtCI inhibition by C458 and C273 activates a mitochondrial stress response conferring neuroprotection against Aβ toxicity.
• These novel compounds exhibit improved drug-like properties and support mtCI inhibitors as a viable disease-modifying strategy for AD.
• The findings highlight the therapeutic potential of targeting mitochondrial function in Alzheimer's disease.