- P7C3 activates NAMPT, elevates intracellular NAD+ and engages SIRT1 and SIRT3 deacetylase cascades to enhance mitochondrial function and redox homeostasis.
- Preclinical studies show broad neuroprotective efficacy in AD, PD, TBI, ischaemic stroke, depression and chemotherapy induced neuropathy independent of disease specific aggregates.
- Clinical translation is challenged by potential on target safety concerns of NAMPT activation, lack of validated biomarkers and prior NAMPT trial failures.
CNS Neurosci Ther. 2026 Sep;32(9):e71139. doi: 10.1002/cns.71139.
ABSTRACT
BACKGROUND: P7C3 compounds are aminopropyl carbazole derivatives identified through phenotypic screening for proneurogenic activity. They directly activate nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD+ salvage pathway. However, a comprehensive synthesis of their mechanisms and therapeutic potential across neurological disorders is currently lacking.
METHODS: A systematic literature review was conducted in PubMed, Web of Science, and Scopus to synthesize the discovery trajectory, structure-activity relationships, molecular mechanisms, and preclinical efficacy of P7C3 compounds. The following keyword combinations were used: (“P7C3” OR “P7C3 compound”) AND (“NAMPT” OR “NAD+” OR “sirtuin” OR “mitochondria”) AND (“neuroprotection” OR “neurodegenerative”).
RESULTS: P7C3 elevates intracellular NAD+ levels, engages SIRT1 and SIRT3 deacetylase cascades, enhances mitochondrial quality control and attenuates oxidative stress. This review discusses the discovery, structure-activity relationships, and molecular mechanisms of P7C3, with a particular emphasis on mitochondrial dynamics and redox homeostasis. The efficacy of P7C3 in preclinical studies was evaluated across Alzheimer’s disease (AD), Parkinson’s disease (PD), traumatic brain injury (TBI), ischemic stroke, depression, and chemotherapy-induced neuropathy. These neuroprotective effects occur independently of disease-specific aggregates. Challenges hindering clinical application include the on-target safety of NAMPT activation given the concurrent development of NAMPT inhibitors for tumorigenesis, the absence of validated predictive biomarkers, and the failure of prior NAMPT-targeting trials.
CONCLUSIONS: P7C3 illustrates how phenotypic screening coupled with target deconvolution can yield therapeutic candidates with potential applications across a broad spectrum of neurological disorders.
PMID:42698301 | DOI:10.1002/cns.71139
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