Description
Summary Abstract
J-147 (N-(2,4-Dimethylphenyl)-2,2,2-trifluoro-N’-[(E)-(3-methoxyphenyl)methylene]acetohydrazide; MW 350.33 Da; cLogP 4.5) is a small-molecule geroprotector synthesized at the Salk Institute for Biological Studies as a rational hybrid of curcumin and cyclohexyl-bisphenol A. Unlike conventional Alzheimer’s therapeutics targeting amyloid-β, J-147 was discovered through phenotypic screening against an array of age-related neuronal stressors simultaneously, yielding a multi-target molecule that addresses aging itself rather than individual pathological hallmarks. Its primary molecular target is the α-subunit of mitochondrial F1F0-ATP synthase (ATP5A), which it partially inhibits (~20–24%) at an EC50 of 20 nM. This mild metabolic stress activates CAMKK2 → AMPK → mTOR inhibition — a canonical longevity pathway shared with caloric restriction and metformin — while independently upregulating BDNF, NGF, and the serotonin-1A (5-HT1A) receptor pathway. In aged APP/swePS1ΔE9 mice with established pathology, three months of J-147 feeding produced profound cognitive rescue, reduced soluble Aβ species, and preserved synaptic-protein levels. In SAMP8 accelerated-aging mice, J-147 reversed molecular signatures of aging to near-youthful transcriptomic and metabolomic profiles. A Phase 1 human clinical trial (NCT03838185) reached completion status; results have not been published.
Clinical Indications
J-147’s pleiotropic mechanisms support investigation in multiple age-driven neurological conditions:
- Alzheimer’s Disease (Disease Modification): Reversed established cognitive deficits in aged transgenic mice with advanced pathology; reduced soluble Aβ40/Aβ42, preserved synaptic spine density, and outperformed donepezil on spatial memory tasks.
- Accelerated and Biological Aging: In SAMP8 mice, J-147 normalized age-related transcriptomic and metabolomic signatures, prevented microvessel leakage at the blood-brain barrier, and extended median Drosophila lifespan by 12.8%.
- Depression and Anxiety: Dose-dependent reduction in immobility in forced-swim and tail-suspension tests via 5-HT1A → cAMP/PKA/pCREB/BDNF signaling; blocked by 5-HT1A antagonist pretreatment.
- Ischemic Stroke: Reduced infarct volume in tMCAO and embolic stroke models; co-administration with tPA significantly reduced hemorrhagic transformation, a major tPA complication.
- Diabetic Neuropathy: Improved nerve conduction velocity and pain nociception in Akita T1D mice via AMPK activation and reduced peripheral inflammatory markers.
Contraindications
- Concurrent mTOR Inhibitors or Metformin: J-147 activates AMPK/mTOR pathway overlap with metformin and rapamycin; pharmacodynamic interactions in co-administration are not characterized in humans.
- Dopaminergic Medications (Parkinson’s / ADHD): Partial dopamine-transporter inhibition has been reported; interaction with dopaminergic agents warrants clinical monitoring.
- Pregnancy: No gestational safety data exist; AMPK pathway modulation during fetal development is not characterized.
- Severe Hepatic Impairment: CeeTox analysis at 90 µM indicates cellular toxicity at concentrations far above therapeutic range; renal/hepatic clearance impairment may narrow the safety margin.
Mechanism of Action (MOA)
J-147 engages mitochondrial bioenergetics as its primary hub and triggers a convergent multi-pathway neuroprotective response:
ATP Synthase Partial Inhibition → Longevity Signaling
J-147 binds the ATP5A (α-subunit) of mitochondrial F1F0-ATP synthase, reducing ATP synthesis activity by ~20% at an EC50 of 20 nM. This mild metabolic stress triggers a calcium → CAMKK2 → AMPK → mTOR-inhibition cascade — an established longevity mechanism shared with caloric restriction — promoting mitochondrial stability, improved energy efficiency, and heightened stress resistance without inducing energy collapse.
Neurotrophic Factor Upregulation
J-147 significantly increases hippocampal BDNF and NGF levels and favorably shifts pro-neurotrophin:mature neurotrophin ratios (↓proBDNF/BDNF, ↓proNGF/NGF). Downstream BDNF-responsive proteins Homer-1 and Egr3 are upregulated, activating long-term potentiation (LTP) and supporting synaptic-spine preservation. This neurotrophic cascade provides the structural basis for observed cognitive rescue independent of amyloid clearance.
5-HT1A Serotonergic Modulation
High-affinity binding to the serotonin-1A receptor (5-HT1A) initiates the cAMP/PKA/pCREB/BDNF transcriptional axis, producing rapid antidepressant-like behavioral effects. This convergence of serotonergic and neurotrophic pathways on a shared BDNF endpoint explains both J-147’s anxiolytic activity and its rapid onset relative to conventional antidepressants.
Anti-Inflammatory & Antioxidant Protection
J-147 reduces microglial activation (Iba-1 downregulation), decreases pro-inflammatory 5-lipoxygenase (5-LOX) and heme oxygenase-1 (HO-1), and protects hippocampal neurons from mitochondrial oxidative stress. This suite of anti-neuroinflammatory effects, inherited from its curcumin pharmacophore, addresses the chronic inflammatory microenvironment characteristic of aging neural tissue.
Key Features & Specifications
J-147’s safety and pharmacokinetic profile compare favorably with CNS drug-development benchmarks:
Chemical Analysis
| Property | Specification Reference Data |
|---|---|
| IUPAC Name | N-(2,4-Dimethylphenyl)-2,2,2-trifluoro-N’-[(E)-(3-methoxyphenyl)methylene]acetohydrazide |
| CAS Number | 1146963-51-0 |
| Molecular Formula | C18H16F3N2O2 (as free base; varies slightly with salt form; MW 350.33 Da) |
| Molecular Weight | 350.33 g/mol |
| PubChem CID | 44206585 |
| Synonyms | J147, J-147, Salk Institute geroprotector, curcumin-CBA hybrid |
| Form / Variation | Capsules (SKU C-050) |
Storage, Safety, and Handling
Storage Protocol
Store capsules at room temperature (15–25 °C) in a sealed, moisture-proof container away from direct light. J-147 is a stable small molecule that does not require refrigeration under standard conditions. Lyophilized bulk material should be stored at 2–8 °C with desiccant.
Handling & Compliance
J-147 is an orally administered small molecule requiring standard laboratory handling precautions. Acute in-vivo toxicity: no adverse effects at oral doses up to 2 g/kg in rodents. CeeTox cellular toxicity threshold: 90 µM — 782–1500× above neuroprotective concentrations. Non-mutagenic (Ames test negative); negative hERG cardiac assay. Long-term consequences of AMPK/mTOR pathway modulation in humans over extended periods remain to be characterized in controlled trials.