J-147

J-147, written J147 in most papers, is a synthetic small-molecule hydrazide from the Salk Institute group of Pamela Maher and David Schubert. Its designers started from curcumin and cyclohexyl-bisphenol A hybrids and chose J147 for potency across several cell assays of age-related nerve cell stress, not for action on one target (Chen et al., 2011).

A molecular target, a subunit of mitochondrial ATP synthase, was reported in 2018 (Goldberg et al., 2018).

Published work on J-147 falls into six areas. Each summary below states the model used. Apart from two registered clinical studies, the evidence is animal and cell data, much of it from the Salk group; the Salk Institute holds the J147 patent, licensed to Abrexa Pharmaceuticals (Currais et al., 2015).

Discovery by phenotypic screening

Rather than starting from one disease target, the Salk group screens compounds in cell assays reflecting several toxicity pathways of the aging brain (Maher, 2020). For J147 these covered loss of trophic support, glutamate-induced oxidative stress (oxytosis), energy failure and amyloid toxicity. From CNB-001, a curcumin derivative, chemists built a hydroxyl-free series by reacting 3-methoxybenzaldehyde with 2,4-dimethylphenylhydrazine; J147, the most active product, had EC50 values of 10 to 200 nM in six assays, where curcumin was at most marginally active (Chen et al., 2011). Models: primary rat neurons and HT22 mouse hippocampal cells.

Memory and Alzheimer's disease mouse models

In normal rodents, J147 raised object recognition scores in rats and object location and Y-maze scores in mice. In APPswe/PS1ΔE9 transgenic mice fed J147 from young adulthood, it prevented water maze deficits; by 10 months of age it had raised hippocampal BDNF and lowered soluble amyloid beta 1-40 and 1-42 without changing insoluble amyloid beta, and plaque load measured at 13 months was slightly lower (Chen et al., 2011).

When the same line aged to 20 months before feeding began, three months of J147 in food reversed cognitive deficits and raised NGF, BDNF and BDNF-responsive proteins; in scopolamine-impaired mice it matched donepezil on short-term memory and outperformed it on spatial memory (Prior et al., 2013). Models: rats and mice.

The molecular target: mitochondrial ATP synthase

Using a protease-protection screen (DARTS) in HT22 cells and a biotin-tagged J147 pull-down, the Salk group identified ATP5A, the alpha subunit of mitochondrial ATP synthase, as a J147 target. In isolated bovine heart mitochondria, J147 inhibited ATP synthase only partially, by about 24 percent at saturation (EC50 20 nM). Knocking down ATP5A reproduced several of its mitochondrial effects, and J147 raised intracellular calcium, activating AMPK through CAMKK2 (Goldberg et al., 2018).

Models: cell lines, isolated mitochondria and mice.

Aging models: SAMP8 mice and fruit flies

Male SAMP8 mice, a senescence-accelerated model of early memory loss, fed J147 from 3 to 10 months of age had fewer cognitive deficits than controls, and markers of vascular pathology, synaptic function and inflammation moved toward the young profile (Currais et al., 2015). J147 also reduced age-associated drift of the hippocampal transcriptome in these mice and, added to fly food at 0.1 or 2 µM, increased male Drosophila longevity by 9.5 and 12.5 percent (Goldberg et al., 2018). Models: mice and fruit flies.

Other rodent models

In mice with streptozotocin-induced diabetes, twice-daily J147 by gavage protected the sciatic nerve from progressive conduction slowing, and one 50 mg/kg gavage briefly reversed established touch-evoked allodynia (Daugherty et al., 2018). In mice, J147 by gavage shortened immobility in the forced swim and tail suspension tests, and a 5-HT1A antagonist blocked the swim test effect (Lian et al., 2018).

In rats, intravenous J147 reduced infarct volume after suture occlusion of the middle cerebral artery, though not alone after embolic stroke, where adding it to tPA at four hours reduced infarct volume, neurological deficits and delayed tPA-associated hemorrhage in an Abrexa-funded study (Jin et al., 2022).

After cortical impact injury in mice, up to seven days of J147 by mouth was followed by better neurological recovery over 35 days and lower endoplasmic reticulum stress markers (Jin et al., 2024). In Zucker rats after abdominal surgery, J147 in food reduced anxiety-like behavior and protected spatial memory, with no anti-inflammatory effect (Oberman et al., 2024). Models: mice and rats.

Metabolism, toxicity screens and clinical development

Because phenyl hydrazides can release potentially carcinogenic aromatic amines or hydrazines, the developers checked J147 metabolism in human and mouse liver microsomes and mouse plasma; neither formed, and its oxidative metabolites were also neuroprotective (Chiruta et al., 2013). In a rat hepatoma cell panel it disturbed cellular functions, mitochondrial function in particular, at high concentrations, and genotoxicity testing was negative (Lapchak et al., 2013).

Abrexa's phase 1 trial, registered for Alzheimer's disease as NCT03838185 (Kepchia et al., 2022), gave single ascending amounts of J147 or placebo to 64 healthy young and elderly volunteers and is listed on ClinicalTrials.gov as completed in February 2020.

No findings are posted there or indexed in PubMed, and a 2023 review noted none had been released (Qiu et al., 2023). In 2026 the registry listed a recruiting, placebo-controlled phase 2 study of intravenous J147 alongside endovascular therapy in acute ischemic stroke (NCT07430917). Sources: cell studies, a review and trial registries.