J147 / Abrexa - LARVOL DELTA

Evidence of Oxytosis/Ferroptosis in Niemann-Pick Disease Type C. (PubMed, Int J Mol Sci) - "Through bioinformatic analyses of pre-symptomatic Npc1-/- Purkinje neurons and in vitro studies using primary dermal fibroblasts derived from NPC patients, we provide evidence suggesting that oxytosis/ferroptosis may play a pathogenic role in NPC. These findings highlight the potential of anti-ferroptotic compounds as a promising therapeutic strategy to mitigate neurodegeneration in NPC and potentially other related disorders."

Journal • CNS Disorders • Frontotemporal Lobar Degeneration • Genetic Disorders • Lysosomal Storage Diseases • Metabolic Disorders • NPC2

J147 Treatment Protects Against Traumatic Brain Injury by Inhibiting Neuronal Endoplasmic Reticulum Stress Potentially via the AMPK/SREBP-1 Pathway. (PubMed, Transl Res) - "Notably, the J147 treatment significantly attenuated AMPK dephosphorylation, SERBP-1 activation, and expression of the ER stress markers. In summary, this study reveals the therapeutic promise of J147 in mitigating secondary brain damage associated with TBI and improving long-term functional recovery by modulating ER stress pathways."

Journal • CNS Disorders • Vascular Neurology • AMPK • ATF4 • EIF2A • EIF2S1 • TCF4

J147 AFFECTS COGNITION AND ANXIETY AFTER SURGERY IN ZUCKER RATS. (PubMed, Physiol Behav) - "Treatment with J147 showed positive effects on behavioral and metabolic parameters, but did not affect (neuro)inflammation. The mixed effect of acute and chronic treatment may suggest a combination for optimal treatment."

Journal • Preclinical • Surgery • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Depression • Genetic Disorders • Inflammation • Obesity • Psychiatry • LCN2

J147 ameliorates sepsis-induced depressive-like behaviors in mice by attenuating neuroinflammation through regulating the TLR4/NF-κB signaling pathway. (PubMed, J Mol Histol) - "J147 administration inhibited bodyweight loss, mortality, microglia activation, and depressive-like behaviors in LPS-treated mice. In conclusion, J147 ameliorated the sepsis-induced depressive-like behaviors induced by neuroinflammation through attenuating the TLR4/NF-κB signaling pathway in microglia."

IO biomarker • Journal • Preclinical • CNS Disorders • Depression • Infectious Disease • Inflammation • Oncology • Psychiatry • Septic Shock • IL1B • IL6 • TLR4 • TNFA

Current evidence for J147 as a potential therapeutic agent in nervous system disease: a narrative review. (PubMed, BMC Neurol) - "In this narrative review, we summarized the background and biochemical properties of J147 and discussed the role and mechanism of J147 in different diseases. Overall, the mechanical attributes of J147 connote it as a potential target for the prevention and treatment of neurological diseases."

Journal • Review • Alzheimer's Disease • Cardiovascular • CNS Disorders • Depression • Dermatology • Diabetic Neuropathy • Hepatology • Infectious Disease • Ischemic stroke • Mood Disorders • Oncology • Pain • Psychiatry

"What are your thoughts on compound J-147?" (@GWelch_1)

J147 Reduces tPA-Induced Brain Hemorrhage in Acute Experimental Stroke in Rats. (PubMed, Front Neurol) - "Our results demonstrate that J147 treatment alone exerts cerebral cytoprotective effects in a suture model of acute ischemic stroke, while in an embolic stroke model co-administration of J147 with tPA reduces delayed tPA-induced intracerebral hemorrhage and confers cerebroprotection. These findings suggest that J147-tPA combination therapy could be a promising approach to improving the treatment of ischemic stroke."

Journal • Preclinical • Cardiovascular • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Immunology • Inflammation • Ischemic stroke • Thrombosis • MMP9

The Alzheimer's disease drug candidate J147 decreases blood plasma fatty acid levels via modulation of AMPK/ACC1 signaling in the liver. (PubMed, Biomed Pharmacother) - "A reduction in FFA levels by J147 was confirmed in HepG2 cells, where activation of the AMPK/ACC1 pathway was seen along with increases in acetyl-CoA and ATP levels which correlated with enhanced cellular bioenergetics. Our data show that J147 targets liver cells to activate the AMPK/ACC1 signaling pathway and preserve energy at the expense of inhibiting FFA synthesis."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • ACACA

The Inhibitory Effect of Curcumin Derivative J147 on Melanogenesis and Melanosome Transport by Facilitating ERK-Mediated MITF Degradation. (PubMed, Front Pharmacol) - "Our findings also suggested that J147 exhibited no cytotoxicity in vitro and in vivo. Taken together, these data confirmed that J147 may prove quite useful as a safer natural skin-whitening agent."

Journal • MITF • MYO5A • Tyrosinase

Activation of monoaminergic system contributes to the antidepressant- and anxiolytic-like effects of J147. (PubMed, Behav Brain Res) - "Moreover, J147-induced significant inhibition of monoamine oxidase A activity. These findings suggest that the antidepressant- and anxiolytic-like effects of J147 might be related to the monoaminergic system by the evidence that high dose of J147 inhibits monoamine oxidase (MAO)-A activity and increases synaptic monoamines in the mouse brain."

Journal • CNS Disorders • Depression • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry

Targeting of intracellular Ca stores as a therapeutic strategy against age-related neurotoxicities. (PubMed, NPJ Aging Mech Dis) - "The molecular basis of these changes was then investigated in cell culture neurotoxicity assays that were the primary screen in the development of J147. Here we show that J147 and its molecular target, ATP synthase, regulate the maintenance of store-operated calcium entry (SOCE) and cell death during acute neurotoxicity."

Journal • Alzheimer's Disease • CNS Disorders

Geroprotective effects of Alzheimer's disease drug candidates. (PubMed, Aging (Albany NY)) - "However, these two organs had distinct, tissue-specific protein level alterations that occurred with age, but in both cases, drug treatments restored a more youthful level. These data show that geroprotective AD drug candidates J147 and CMS121 prevent age-associated disease in both brain and kidney, and that their apparent mode of action in each tissue is distinct."

Journal • Alzheimer's Disease • Chronic Kidney Disease • CNS Disorders • Cognitive Disorders • Dementia • Immunology • Inflammation • Nephrology • Renal Disease

Targeting of intracellular Ca stores as a therapeutic strategy against age-related neurotoxicities. (PubMed, NPJ Aging Mech Dis) - "The molecular basis of these changes was then investigated in cell culture neurotoxicity assays that were the primary screen in the development of J147. Here we show that J147 and its molecular target, ATP synthase, regulate the maintenance of store-operated calcium entry (SOCE) and cell death during acute neurotoxicity."

Journal • Alzheimer's Disease • CNS Disorders

Study to Assess the Safety, Tolerability and Pharmacokinetics of Single Ascending Oral Doses of J147 (clinicaltrials.gov) - P1; N=64; Completed; Sponsor: Abrexa Pharmaceuticals, Inc.; Recruiting ➔ Completed; Trial primary completion date: Oct 2019 ➔ Feb 2020

Clinical • Trial completion • Trial primary completion date • Alzheimer's Disease • CNS Disorders

Sub-Acute Treatment of Curcumin Derivative J147 Ameliorates Depression-Like Behavior Through 5-HT-Mediated cAMP Signaling. (PubMed, Front Neurosci) - "The results suggest that J147 induces rapid antidepressant-like effects during a 3-day treatment period without inducing drug tolerance. These effects might be mediated by 5-HT-dependent cAMP/PKA/pCREB/BDNF signaling."

Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry • BDNF

In Silico Repurposing of J147 for Neonatal Encephalopathy Treatment: Exploring Molecular Mechanisms of Mutant Mitochondrial ATP Synthase. (PubMed, Curr Pharm Biotechnol) - "Findings suggest that J147 can stabilize the mutant protein and restore it to a similar structural state as the wild-type which depicts functionality. These details could be employed in drug design for potential drug resistance cases due to mATPase mutations that may present in the future."

Journal • Alzheimer's Disease • CNS Disorders

Elevating acetyl-CoA levels reduces aspects of brain aging. (PubMed, Elife) - "CMS121 and J147 increased the levels of acetyl-CoA in cell culture and mice via the inhibition of acetyl-CoA carboxylase 1 (ACC1), resulting in neuroprotection and increased acetylation of histone H3K9 in SAMP8 mice, a site linked to memory enhancement. These data show that targeting specific metabolic aspects of the aging brain could result in treatments for dementia."

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Broadening the horizon: Integrative pharmacophore-based and cheminformatics screening of novel chemical modulators of mitochondria ATP synthase towards interventive Alzheimer's disease therapy. (PubMed, Med Hypotheses) - "The proven efficacy of J147 in the treatment of Alzheimer's disease (AD) has been emphatic, particularly since its selective modulatory roles towards mitochondrial ATP synthase (mATPase) were defined...As developed in this study, the most extrapolative pharmacophore model of the selected hits encompassed three electron donors and one electron acceptor. We speculate that these findings will be fundamental to the reformation of anti-AD drug discovery procedures."

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The mitochondrial ATP synthase is a shared drug target for aging and dementia. (PubMed, Aging Cell) - "...Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147...Our results link aging and age-associated dementia through ATP synthase, a molecular drug target that can potentially be exploited for the suppression of both. These findings demonstrate that novel screens for new AD drug candidates identify compounds that act on established aging pathways, suggesting an unexpectedly close molecular relationship between the two."

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Deciphering the "elixir of life": Dynamic perspectives into the allosteric modulation of mitochondrial ATP synthase by J147, a novel drug in the treatment of Alzheimer's disease. (PubMed, Chem Biodivers) - "Furthermore, J147 exhibited favourable binding at the allosteric site of mATP synthase with considerable electrostatic energy contributions from Gln215, Gly217, Thr219, Asp312, Asp313, Glu371 and Arg406. These findings provide details on the possible effects of J147 on mitochondrial bioenergetics, which could facilitate the structure-based design of novel small-molecule modulators of mATP synthase in the management of Alzheimer's disease and other neurodegenerative disorders."

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