Tag: Curcumin and cyclohexyl-bisphenol-A hybrid; mitochondrial ATP synthase modulator

J-147 (CAS 1146963-51-0; molecular formula C18H17F3N2O2; molecular weight 350.33) is a synthetic phenyl hydrazide small molecule developed at the Salk Institute for Biological Studies in the laboratory of David Schubert through iterative phenotypic optimization beginning from the natural product curcumin. First reported by Chen et al. in 2011, J-147 was selected from a combinatorial chemical library on the basis of nanomolar potency across six cell-based assays modeling age-associated neurotoxicities: trophic factor withdrawal (EC50 25 nM), oxidative stress (EC50 10 to 200 nM), glucose starvation, chemical ischemia, and amyloid-beta 1-42 toxicity. The compound represents approximately 100-fold greater potency than its immediate precursor CNB-001 and vastly greater potency and bioavailability than curcumin itself, which was inactive in the selection assays at achievable concentrations.

The molecular target of J-147 was identified in 2018 by Goldberg et al. as the alpha-F1 subunit of mitochondrial ATP synthase (ATP5A), using drug affinity responsive target stability (DARTS) and biotinylated affinity precipitation approaches. J-147 partially inhibits ATP synthase activity with an EC50 of approximately 20 nM and saturates at approximately 23.6 percent inhibition, producing a dose-dependent increase in cytosolic calcium that activates calcium/calmodulin-dependent protein kinase kinase beta (CAMKK2), which phosphorylates AMP-activated protein kinase (AMPK) at threonine 172. The resulting AMPK activation modulates mammalian target of rapamycin complex 1 (mTORC1) signaling, acetyl-CoA carboxylase 1 (ACC1) activity, and downstream metabolic pathways linked to both aging and neurodegeneration. ATP5A knockdown phenocopies J-147 across multiple neuroprotection assays, and J-147 provides no additional protection in ATP5A-knockdown cells, confirming target engagement specificity.

In preclinical models, J-147 administered orally at 200 ppm in food (approximately 10 mg/kg/day) prevents cognitive decline in young APP/swePS1-deltaE9 transgenic mice over 7 months, preserves synaptic proteins (drebrin, synapsin-1, synaptophysin), reduces soluble amyloid-beta 1-40 and 1-42, increases brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), facilitates long-term potentiation at concentrations of 0.01 to 1 micromolar, and reduces oxidative stress and neuroinflammation markers. In aged (20-month) APP/PS1 mice, 3 months of J-147 treatment reverses established cognitive deficits in water maze, fear conditioning, and elevated plus maze paradigms. In the SAMP8 senescence-accelerated mouse model, J-147 attenuates age-associated hippocampal transcriptional drift by approximately 6 percent (P less than 10 to the negative 10). In Drosophila melanogaster, J-147 extends median lifespan by 9.5 to 12.5 percent.

Pharmacokinetically, J-147 demonstrates 28 percent oral bioavailability in mice, a plasma half-life of 1.5 hours, a brain half-life of 2.5 hours, brain concentrations of approximately 600 nM at 2 hours after a 20 mg/kg oral dose (5- to 10-fold above its neuroprotective EC50), and a brain-to-plasma ratio of approximately 0.5. The compound is classified as having high blood-brain barrier penetration by the MDCK-MDRI cell culture model. Safety evaluation demonstrates no genotoxicity (Ames test negative to 0.36 mM), no acute toxicity in rats at 2 g/kg, no hERG channel inhibition, a CeeTox predicted toxicity value of 90 micromolar (yielding a therapeutic safety window of 782 to 3600-fold over efficacy concentrations), and no significant off-target activity across more than 60 CNS receptors, 352 protein kinases, and extensive enzyme panels. The sole notable off-target interactions are modest dopamine transporter (EC50 0.649 micromolar) and monoamine oxidase B (EC50 1.88 micromolar) activities at concentrations 6.5- to 19-fold above the neuroprotective range. A Phase 1 randomized double-blind placebo-controlled clinical trial (NCT03838185) was initiated in February 2019 by Abrexa Pharmaceuticals and completed in February 2020; results have not been published. The compound is not approved by any regulatory authority and is supplied exclusively as a research compound.