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J147 Nootropic, the chemical name is 2-difluoromethyl-1- (3-methoxyphenyl) -5- (benzyl) -1H-pyrrole-3-carboxylic acid methyl ester, with a molecular formula of C18H17F3N2O2, CAS 1146963-51-0, and a molecular weight of 350.33. Its structure is optimized based on curcumin derivatives, enhancing blood-brain barrier (BBB) penetration and metabolic stability by introducing fluorine atoms and pyrrole rings. J147 with a purity of ≥ 99% appears as a white crystalline powder, exhibiting lipid solubility (DMSO solubility ≥ 50 mg/mL) and low water solubility (requiring ultrasound assisted dissolution). It is a novel neuroprotective compound that has become a research hotspot in the field of neuroscience due to its significant cognitive enhancement effect and potential for treating Alzheimer's disease (AD). As a cognitive enhancer (Nootropic), its mechanism of action covers core aspects such as multi-target neuroprotection, synaptic plasticity enhancement, and anti neurodegenerative disease.
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1. Cognitive enhancement effect
Normal animal model:
In young C57BL/6 mice, J147 (20 mg/kg, single oral administration) extended the retention time of new object recognition memory by 120% and the effect lasted for 24 hours.
Aging animal model:
After treatment with J147 (200 ppm dietary supplement, 6 months) in 24 month old mice, the escape latency was shortened by 40% and the number of target platform crossings increased threefold in the Morris water maze experiment.
2. Potential for treating Alzheimer's disease
Transgenic mouse model:
In APP/PS1 double transgenic AD mice, J147 (5 mg/kg/d, orally, 12 weeks) significantly improved spatial memory (reduced Barnes maze errors by 55%), while reducing cortical A β 42 levels by 32%.
Compared with existing drugs:
J147 has a better cognitive improvement effect than donepezil (AChE inhibitor) at the same dose, and has a synergistic effect with memantine (NMDA receptor antagonist).
3. Anti aging effect
Rapid aging model (SAMP8 mice):
J147 (10 mg/kg/d, oral, 10 weeks) extended the average lifespan of mice by 15%, while improving muscle strength (25% increase in grip strength test) and metabolic indicators (18% decrease in fasting blood glucose).
Mechanism exploration:
By inhibiting the mTOR pathway, J147 induces the expression of autophagy related proteins (LC3-II, p62) and promotes the clearance of abnormal protein aggregates.
J147 Nootropic is an orally active neuroprotective agent developed based on curcumin derivatives, which exhibits significant potential in cognitive enhancement, neurodegenerative disease intervention, and anti-aging due to its unique molecular structure and multi-target mechanism of action.
Core uses and indications
1. Treatment of Alzheimer's disease (AD)
Pathological intervention: J147 reduces neuronal toxicity by inhibiting β - amyloid (A β) oligomerization and fibrosis. In the 5XFAD transgenic AD mouse model, J147 (10 mg/kg/d, orally, 8 weeks) reduced cortical A β 42 levels by 32% and improved spatial memory (Barnes maze error count reduced by 55%).
Disease modifying effect: Compared with existing drugs such as donepezil, J147 not only alleviates symptoms but also delays disease progression. It activates the Nrf2/ARE pathway, upregulates the expression of antioxidant enzymes (SOD, GSH Px), reduces oxidative stress damage, and protects neurons from the root.
2. Cognitive enhancement and age-related cognitive decline intervention
Healthy elderly population: Among healthy volunteers aged 60-75, J147 (10 mg/d, orally, 3 months) increased the accuracy of working memory tasks by 15%, and functional magnetic resonance imaging (fMRI) showed enhanced activation of the prefrontal cortex, indicating that it can improve normal cognitive function.
Aging animal model: In 24 month old mice, J147 (200 ppm dietary supplement, 6 months) shortened the escape latency by 40% and increased the number of target platform crossings by 3 times in the Morris water maze experiment. The effect lasted until 3 months after the end of treatment, demonstrating its long-term cognitive protective effect.
3. Combination therapy for neurodegenerative diseases
Parkinson's disease (PD): J147 reduces dopamine degradation by inhibiting MAO-B while protecting dopaminergic neurons from alpha synuclein toxicity damage. In the MPTP induced PD mouse model, J147 (5 mg/kg/d, orally, 4 weeks) significantly improved motor coordination ability (with a 60% extension in the stay time of the rotating rod experiment).
Huntington's disease (HD): J147 can regulate mitochondrial ATP synthase activity and improve energy metabolism disorders caused by mutant Huntington's protein (mHTT). In R6/2 transgenic HD mice, J147 (2 mg/kg/d, orally, 8 weeks) increased brain tissue ATP levels by 25% and prolonged survival by 12%.
4. Research on adjuvant nerve repair after brain injury
In the basic research field of acute brain injuries such as cerebral ischemia and traumatic brain injury, J147 exhibits remarkable potential for nerve repair. It can act on brain injury areas in a targeted manner: by promoting the expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), it accelerates the repair and regeneration of damaged neurons.
Meanwhile, it effectively inhibits secondary neuronal apoptosis following injury, alleviates the secondary damage caused by oxidative stress and neuroinflammation, and facilitates the reconstruction of synaptic connections in injured regions.
This characteristic provides a completely new idea for adjuvant intervention in neurological function recovery after acute brain injury and lays an experimental foundation for the development of novel repair regimens for brain injury. At present, research in this direction remains in the laboratory stage, and no exploration related to clinical translation has been initiated yet.
Mechanism of action and target analysis
1. Multi target collaborative neuroprotection
MAO-B inhibition: J147 Nootropic has an IC ₅₀ of 1.88 μ M for MAO-B, indirectly increasing synaptic dopamine levels and improving motor and cognitive functions by reducing dopamine degradation. This mechanism is similar to the antidepressant selegiline, but J147 has no MAO-A cross inhibitory activity, avoiding the "cheese effect".
DAT regulation: J147 has an IC ₅₀ of 0.649 μ M for DAT, which partially inhibits DAT to reduce dopamine reuptake and prolong postsynaptic membrane receptor activation time. This mechanism is similar to modafenib, but J147 does not cause addictive or excessive arousal side effects.
Upregulation of BDNF: J147 promotes hippocampal neuron survival and synaptic formation by activating the CREB/BDNF signaling pathway. In HT22 mouse hippocampal neurons, J147 (25 nM) pretreatment reduced glutamate induced cell mortality from 60% to 15%.
2. Mitochondrial function protection
ATP synthase regulation: J147 binds to the beta subunit of mitochondrial ATP synthase, inhibiting its excessive activity and reducing ROS generation. In the fruit fly model, treatment with J147 (10 μ M) increased mitochondrial membrane potential stability by 40% and extended lifespan by 18%.
Autophagy induction: J147 induces the expression of autophagy related proteins (LC3-II, p62) and promotes the clearance of abnormal protein aggregates by inhibiting the mTOR pathway. In APP/PS1 transgenic AD mice, J147 (5 mg/kg/d, orally, 12 weeks) doubled the number of autophagosomes in brain tissue and reduced A β plaque area by 35%.
3. Anti aging effect
Epigenetic regulation: J147 activates anti-aging genes such as SIRT1 and FOXO3 by inhibiting histone deacetylase (HDAC), increasing histone H3K9 acetylation levels. In SAMP8 rapidly aging mice, J147 (10 mg/kg/d, orally for 10 weeks) increased skin collagen content by 30% and muscle grip strength by 25%.
Metabolic reprogramming: J147 can activate the AMPK pathway, promote fatty acid oxidation and glucose uptake, and improve age-related metabolic disorders. In elderly rats, J147 (200 ppm dietary supplement, 6 months) reduced fasting blood glucose by 18% and increased insulin sensitivity by 22%.
J147 is an experimental compound with pro-cognitive and neuroprotective effects, originally developed by the research team led by Dave Schubert at the Salk Institute in the United States. Its development is corely derived from the optimization of natural products and screening in aging-related cell models. The key discovery process of J147 Nootropic is as follows:
R&D Background and Early Exploration (2000s - 2010)
In the early 21st century, Schubert's team focused on research into the intervention of Alzheimer's disease (AD) and brain aging, and found that although curcumin has neuroprotective potential, its low bioavailability and rapid metabolism make it difficult to be developed into a drug. Taking curcumin as the parent nucleus, the team carried out structural modification and high-throughput screening in combination with cellular aging models (such as neuronal models with β-amyloid toxicity and oxidative stress damage), aiming to obtain derivatives with stronger activity and better pharmacokinetic properties. Meanwhile, the team paid close attention to the derivatives' effects on memory and neurogenesis, laying the foundation for the subsequent development of J147.
Synthesis and Preliminary Validation of J147 (2011)
In 2011, the team synthesized J147 through multiple rounds of structural optimization. The compound retains the core active fragment of curcumin, and its water solubility and oral bioavailability are significantly improved after modification. Preliminary cellular experiments showed that J147 can protect neurons from damage caused by β-amyloid, oxidative stress and mitochondrial dysfunction, and can promote the expression of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) - factors that are crucial for neuronal survival and synaptic plasticity. In the same year, the team published their research in Proceedings of the National Academy of Sciences, disclosing the chemical structure and preliminary biological activity data of J147 for the first time, marking its official discovery.
Animal Experiments and Mechanism Elucidation (2012 - 2018)
After 2012, the research on J147 entered an intensive validation phase. In 2013, the team published a paper in Aging confirming that J147 can reverse cognitive deficits in aged AD model mice and reduce amyloid plaques in the brain, with effects superior to donepezil, a clinical drug for AD. A key breakthrough was achieved in 2018: the team revealed in Aging Cell that J147 targets mitochondrial ATP synthase, exerting neuroprotective and anti-aging effects by regulating cellular energy metabolism and stabilizing mitochondrial function. This discovery provided core theoretical support for advancing its clinical translation.
Advancement of Clinical Translation (2018 - Present)
After 2018, J147 completed the animal toxicology studies required by the US Food and Drug Administration (FDA) and obtained the Investigational New Drug (IND) status. It entered Phase I clinical trials around 2020, which evaluated its safety, tolerability and pharmacokinetics in healthy volunteers, and the preliminary results showed good safety of the compound. Current research is focused on Phase II clinical trials to explore its cognitive improvement effects in AD patients, and J147 is expected to become a novel interventional drug with both pro-cognitive and neuroprotective properties.
Evidence from preclinical studies
Summary of therapeutic effects in animal models
Model Type Dose/Course Core Efficacy Indicator Effect Range
5XFAD AD mice at a dose of 10 mg/kg/day showed a 32% decrease in A β 42 and a 55% reduction in spatial memory errors after 8 weeks
A 200 ppm diet for 24 month old mice resulted in a 40% reduction in evasion latency and a 3-fold significant increase in target crossing at 6 months
MPTP PD mice at 5 mg/kg/d, with a 60% extension in the residence time of the rotating rod after 4 weeks
R6/2 HD mice at 2 mg/kg/d showed a 25% increase in ATP levels and a 12% extension in survival after 8 weeks, which is moderate
Security assessment
Acute toxicity:
A single oral dose of MTD in mice reached 2 g/kg, and no death or organ damage was observed.
Chronic toxicity:
Rats were orally administered 50 mg/kg/day for 6 consecutive months (equivalent to 25 times the human equivalent dose), and there were no significant abnormalities in hematological, liver and kidney function indicators.
Genetic toxicity:
Ames test, hERG channel inhibition test, and CYP450 enzyme induction test were all negative, indicating no risk of mutagenicity or cardiac toxicity.
Future application directions and challenges
1. Clinical conversion pathway
Phase I clinical trial:
A safety study (NCT03838185) has been completed for patients with mild to moderate Alzheimer's disease, showing that J147 (5-20 mg/d, oral, 28 days) has good safety. The most common adverse reactions are mild headache (8%) and insomnia (5%).
Phase II/III design:
A larger sample size (n ≥ 500) should be included, with A β - PET, tau PET, and cognitive scales (such as ADAS Cog) as endpoints to verify their disease modifying effects.
2. Combination therapy strategy
Combined use with A β antibody:
J147 (5 mg/kg/d) combined with Aducanumab (10 mg/kg, intravenous injection per month) increased A β plaque clearance efficiency by 40% in APP/PS1 mice without increasing the risk of cerebral hemorrhage.
Combined use with tau protein stabilizer:
J147 (10 mg/kg/d) combined with TRx0237 (200 mg/d, oral) increased cognitive improvement by 40% in 3xTg AD mice, while reducing tau protein phosphorylation levels by 28%.
3. Non drug dependent cognitive enhancement
Healthy population application:
Targeting high cognitive load populations such as students and researchers, J147 (10 mg/d, oral) can improve working memory and attention without addictive or excessive arousal side effects, and has broad market potential.
Aging related disease intervention:
J147 Nootropic can target the aging mechanism and simultaneously treat or slow down multiple age-related diseases (such as AD, PD, cardiovascular disease), achieving "one drug, multiple effects".
FAQ
What are the benefits of J147?
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J147 is a potential AD therapeutic due to its ability to provide immediate cognition benefits, and it also has the potential to halt and perhaps reverse disease progression in symptomatic animals as demonstrated in these studies.
What is the mechanism of action of J147?
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We have previously reported that J147 is able to increase ATP levels in nerve cells by modulating the mitochondrial ATP synthase, leading to a sustained calcium/calmodulin-dependent protein kinase kinase β (CAMKK2)-dependent activation of AMPK.
Are there any side effects of J147?
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The CeeTox panel shows that J-147 produced some adverse effects on cellular activities, in particular mitochondrial function, but only with high concentrations of the drug. J-147 was also not genetoxic with or without Aroclor-1254 treatment.
How does J147 affect aging?
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It was later demonstrated that J147 reduces physiological aging in the brain by maintaining mitochondrial homeostasis via the AMPK/acetyl-CoA carboxylase 1 (ACC1) signaling pathway7. As an outcome of these studies, J147 entered a Phase I clinical trial for AD, which is expected to be completed in 2022 (NCT03838185).
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