<br/> A novel neuroprotective small molecule was discovered using a target-agnostic <i>in vivo</i> screen in living mice. The potency and drug-like properties of this compound, P7C3, were optimized through a medicinal chemistry campaign, providing analogs for detailed examination. Improved versions, such as (-)-P7C3-S243 and P7C3-A20, displayed neuroprotective properties in rodent models of Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury and age-related cognitive decline. Derivatives appended with photo-crosslinking moieties revealed that P7C3 compounds bind and activate the rate-limiting enzyme in the NAD salvage pathway. Our results indicate that unbiased, in vivo screens might provide starting points for the development of treatments for neurodegenerative diseases as well as tools to study the biology underlying these disorders.

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P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases

249th National Meeting (2015)

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<br /> P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases