J-147

J-147 (CAS 1146963-51-0; molecular formula C18H17F3N4O2; molecular weight 378.35) is a small-molecule hybrid compound designed at the Salk Institute by David Schubert and colleagues as a chemical fusion of structural elements from curcumin and cyclohexyl-bisphenol A (CNB-001, an earlier Salk-developed compound). The design intent was to retain the broad neuroprotective activity attributed to curcumin while improving pharmacokinetics: oral bioavailability of the parent curcumin is severely limited by poor aqueous solubility and rapid hepatic metabolism, while J-147 demonstrates approximately 80 percent oral bioavailability and substantial central nervous system exposure in rodent models. The principal molecular target identified through chemical biology pulldown experiments published in 2018 is the alpha subunit of mitochondrial ATP synthase (ATP5A); J-147 binding modulates ATP synthase function and produces downstream effects on mitochondrial calcium uptake, NAD/NADH ratio, and cellular redox state consistent with hormetic mitochondrial stimulation. Behavioral effects in rodent models include reversal of cognitive deficits in aged senescence-accelerated mice, in APPswe/PS1dE9 transgenic Alzheimer's models, and in models of accelerated aging. The compound entered Phase 1 clinical trials for Alzheimer's disease through Abrexa Pharmaceuticals in 2018 (NCT03838185). Phase 1 published results report acceptable safety in healthy volunteers and dose-dependent target engagement; no Phase 2 data have been published as of the most recent monograph revision. The compound represents a structural class distinct from the amyloid-clearing antibodies (lecanemab, donanemab) that have dominated recent Alzheimer's clinical development; the proposed mechanism is upstream of plaque biology and operates on cellular bioenergetics. J-147 is not approved by any regulatory authority. Stability of solid material is good at refrigerated storage; aqueous formulations require co-solvent owing to limited water solubility.