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https://www.readbyqxmd.com/read/27149904/selecting-for-neurogenic-potential-as-an-alternative-for-alzheimer-s-disease-drug%C3%A2-discovery
#1
Marguerite Prior, Joshua Goldberg, Chandramouli Chiruta, Catherine Farrokhi, Mariya Kopynets, Amanda J Roberts, David Schubert
INTRODUCTION: Neurons die in Alzheimer's disease (AD) and are not effectively replaced. An alternative approach to maintain nerve cell number is to identify compounds that stimulate the proliferation of endogenous neural stem cells in old individuals to replace lost neurons. However, unless a neurogenic drug is also neuroprotective, the replacement of lost neurons will not be sufficient to stop disease progression. METHODS: The neuroprotective AD drug candidate J147 is shown to enhance memory, improve dendritic structure, and stimulate cell division in germinal regions of the brains of very old mice...
June 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
https://www.readbyqxmd.com/read/26564964/a-comprehensive-multiomics-approach-toward-understanding-the-relationship-between-aging-and-dementia
#2
Antonio Currais, Joshua Goldberg, Catherine Farrokhi, Max Chang, Marguerite Prior, Richard Dargusch, Daniel Daugherty, Aaron Armando, Oswald Quehenberger, Pamela Maher, David Schubert
Because age is the greatest risk factor for sporadic Alzheimer's disease (AD), phenotypic screens based upon old age-associated brain toxicities were used to develop the potent neurotrophic drug J147. Since certain aspects of aging may be primary cause of AD, we hypothesized that J147 would be effective against AD-associated pathology in rapidly aging SAMP8 mice and could be used to identify some of the molecular contributions of aging to AD. An inclusive and integrative multiomics approach was used to investigate protein and gene expression, metabolite levels, and cognition in old and young SAMP8 mice...
November 2015: Aging
https://www.readbyqxmd.com/read/26303522/dicyanovinyl-substituted-j147-analogue-inhibits-oligomerization-and-fibrillation-of-%C3%AE-amyloid-peptides-and-protects-neuronal-cells-from-%C3%AE-amyloid-induced-cytotoxicity
#3
Kyoungdo Kim, Kwang-su Park, Mi Kyoung Kim, Hyunah Choo, Youhoon Chong
A series of novel J147 derivatives were synthesized, and their inhibitory activities against β-amyloid (Aβ) aggregation and toxicity were evaluated by using the oligomer-specific antibody assay, the thioflavin-T fluorescence assay, and a cell viability assay in the transformed SH-SY5Y cell culture. Among the synthesized J147 derivatives, 3j with a 2,2-dicyanovinyl substituent showed the most potent inhibitory activity against Aβ42 oligomerization (IC50 = 17.3 μM) and Aβ42 fibrillization (IC50 = 10.5 μM), and disassembled the preformed Aβ42 fibrils with an EC50 of 10...
October 7, 2015: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/25982925/a-potent-multi-functional-neuroprotective-derivative-of-tetramethylpyrazine
#4
Hai-Yun Chen, Da-Ping Xu, Guo-Lian Tan, Wei Cai, Gao-Xiao Zhang, Wei Cui, Jin-Zhao Wang, Cheng Long, Ye-Wei Sun, Pei Yu, Karl Wahkeung Tsim, Zai-Jun Zhang, Yi-Fan Han, Yu-Qiang Wang
Neurodegenerative disorders are one of the leading causes of death among the elderly. Therapeutic approaches with a single target have proven unsuccessful in treating these diseases. Structural combination of multi-functional compounds may lead to a molecule with multiple properties. In this study, we designed and synthesized T-006, a novel analog derived from two multi-functional neuroprotective chemicals, tetramethylpyrazine and J147. The methoxyphenyl group of J147 was replaced by tetramethylpyrazine. Bioactivity evaluation showed that T-006 at very low concentrations had multi-functional neuroprotective effects including rescuing iodoacetic acid-induced neuronal loss, preventing oxidative stress-induced neurotoxicity and reducing glutamate-induced excitotoxicity in vitro...
August 2015: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/23673233/the-neurotrophic-compound-j147-reverses-cognitive-impairment-in-aged-alzheimer-s-disease-mice
#5
Marguerite Prior, Richard Dargusch, Jennifer L Ehren, Chandramouli Chiruta, David Schubert
INTRODUCTION: Despite years of research, there are no disease-modifying drugs for Alzheimer's disease (AD), a fatal, age-related neurodegenerative disorder. Screening for potential therapeutics in rodent models of AD has generally relied on testing compounds before pathology is present, thereby modeling disease prevention rather than disease modification. Furthermore, this approach to screening does not reflect the clinical presentation of AD patients which could explain the failure to translate compounds identified as beneficial in animal models to disease modifying compounds in clinical trials...
2013: Alzheimer's Research & Therapy
https://www.readbyqxmd.com/read/23582448/metabolism-of-a-potent-neuroprotective-hydrazide
#6
Chandramouli Chiruta, Yanrong Zhao, Fangling Tang, Tao Wang, David Schubert
Using a drug discovery scheme for Alzheimer's disease (AD) that is based upon multiple pathologies of old age, we identified a potent compound with efficacy in rodent memory and AD animal models. Since this compound, J147, is a phenyl hydrazide, there was concern that it can be metabolized to aromatic amines/hydrazines that are potentially carcinogenic. To explore this possibility, we examined the metabolites of J147 in human and mouse microsomes and mouse plasma. It is shown that J147 is not metabolized to aromatic amines or hydrazines, that the scaffold is exceptionally stable, and that the oxidative metabolites are also neuroprotective...
May 15, 2013: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/23237833/the-first-synthesis-of-11c-j147-a-new-potential-pet-agent-for-imaging-of-alzheimer-s-disease
#7
Min Wang, Mingzhang Gao, Qi-Huang Zheng
J147 was synthesized from 2,4-dimethylphenylhydrazine hydrochloride and 3-methoxybenzaldehyde in 2 steps with 71% overall yield. The precursor desmethyl-J147 was synthesized from 3-hydroxybenzaldehyde and 2,4-dimethylphenylhydrazine hydrochloride in 4 steps with 63% overall yield. [(11)C]J147 was prepared from desmethyl-J147 with [(11)C]CH(3)OTf through O-[(11)C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 35-50% radiochemical yield based on [(11)C]CO(2) and decay corrected to end of bombardment (EOB), with 370-740 GBq/μmol specific activity at EOB...
January 15, 2013: Bioorganic & Medicinal Chemistry Letters
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