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Jonathan D Low, Michael D Bartberger, Yuan Cheng, Doug Whittington, Quifen Xue, Stephen Wood, Jennifer R Allen, Ana E Minatti
The diastereoselective synthesis and structure activity relationship (SAR) of a series of fused cyclopropyl-3-amino-2,4-oxazine (2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine)-containing BACE inhibitors is described. Through these efforts compound 2 was identified as a potent (cell IC50 = 15 nM) BACE inhibitor with acceptable ADME properties. When tested in vivo, compound 2 demonstrated a significant reduction of brain and cerebral spinal fluid (CSF) Aβ40 levels (46% and 66%, respectively) in a rat pharmacodynamic study and thus represents a suitable starting point for the further development of in vivo efficacious compounds for the treatment of Alzheimer's disease...
February 1, 2018: Bioorganic & Medicinal Chemistry Letters
WonHee Kim, Liang Ma, Selene Lomoio, Rachel Willen, Sylvia Lombardo, Jinghui Dong, Philip G Haydon, Giuseppina Tesco
BACKGROUND: β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in the production of amyloid beta (Aβ), the toxic peptide that accumulates in the brains of Alzheimer's disease (AD) patients. Our previous studies have shown that the clathrin adaptor Golgi-localized γ-ear-containing ARF binding protein 3 (GGA3) plays a key role in the trafficking of BACE1 to lysosomes, where it is normally degraded. GGA3 depletion results in BACE1 stabilization both in vitro and in vivo...
February 2, 2018: Molecular Neurodegeneration
Eva Bace, Michal Karpisek, David Stejskal, Hana Kotolova, Viktor Ruzicka, Martina Hlozankova
No abstract text is available yet for this article.
August 2017: Atherosclerosis
Lei Zhang, Laigao Chen, Jason K Dutra, Elizabeth M Beck, Sangram Nag, Akihiro Takano, Nahid Amini, Ryosuke Arakawa, Michael A Brodney, Leanne M Buzon, Shawn D Doran, Lorraine F Lanyon, Timothy J McCarthy, Kelly R Bales, Charles E Nolan, Brian T O'Neill, Klaas Schildknegt, Christer Halldin, Anabella Villalobos
Alzheimer's disease (AD) is characterized by accumulation of β-amyloid (Aβ) plaques and neurofibrillary tau tangles in brain. β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a key role in the generation of Aβ fragments via extracellular cleavage of the amyloid precursor protein (APP). We became interested in developing a BACE1 PET ligand to facilitate clinical assessment of BACE1 inhibitors and explore its potential in the profiling and selection of patients for AD trials. Using a set of PET ligand design parameters, compound 3 (PF-06684511) was rapidly identified as a lead with favorable in vitro attributes and structural handles for PET radiolabeling...
January 22, 2018: Journal of Medicinal Chemistry
Angela Rampa, Silvia Gobbi, Rita Maria Concetta Di Martino, Federica Belluti, Alessandra Bisi
In industrialized countries, Alzheimer's disease represents the most devastating neurodegenerative disorder in elderly people and the search for a disease modifying agent is still justified by this unmet need. Several possible targets have been explored to find an appropriate drug therapy, and in this review dual inhibitors of beta secretase and glycogen synthase kinase 3, recently reported in literature, will be appraised. Applying a ligand-based approach, the triazinone core emerged as a suitable scaffold to simultaneously bind the aspartic dyad of BACE-1 and the ATP site of GSK-3β, leading to a series of small molecules endowed with a balanced micromolar affinity and a promising pharmacokinetic profile...
January 12, 2018: Current Topics in Medicinal Chemistry
Jonathan S Schurman, Volodymyr Trotsiuk, Radek Bače, Vojtěch Čada, Shawn Fraver, Pavel Janda, Dominik Kulakowski, Jana Labusova, Martin Mikoláš, Thomas A Nagel, Rupert Seidl, Michal Synek, Kristýna Svobodová, Oleh Chaskovskyy, Marius Teodosiu, Miroslav Svoboda
Determining the drivers of shifting forest disturbance rates remains a pressing global change issue. Large-scale forest dynamics are commonly assumed to be climate driven, but appropriately scaled disturbance histories are rarely available to assess how disturbance legacies alter subsequent disturbance rates and the climate sensitivity of disturbance. We compiled multiple tree-ring based disturbance histories from primary Picea abies forest fragments distributed throughout five European landscapes spanning the Bohemian Forest and the Carpathian Mountains...
January 11, 2018: Global Change Biology
Akhil Kumar, Gaurava Srivastava, Arvind S Negi, Ashok Sharma
BACE-1 and GSK-3β both are potential therapeutic drug targets for Alzheimer's disease. Recently, both these targets received attention for designing dual inhibitors. Till now only two scaffolds (triazinone and curcumin) derivatives have been reported as BACE-1 and GSK-3β dual inhibitors. In our previous work, we have reported first in class dual inhibitor for BACE-1 and GSK-3β. In this study we have explored other naphthofuran derivatives for their potential to inhibit BACE-1 and GSK-3β through docking, molecular dynamics, binding energy (MM-PBSA)...
January 8, 2018: Journal of Biomolecular Structure & Dynamics
Jonathan Orf, Scot Walker
Alzheimer's disease (AD) is a common disease in the United States with almost 10% of people older than 65 suffering from the disease. A few drugs provide some improvement in mental function in mild-to-moderate disease, but no treatments are available to prevent the development of AD. Two new classes of drugs being investigated for the treatment or prevention of AD include drugs to decrease beta amyloid accumulation and Tau protein aggregation inhibitors. After disappointing results for treatment of AD, both classes are being tested in prevention trials...
December 2017: Hospital Pharmacy
Wai Yin Vivien Chiu, Alex Chun Koon, Jacky Chi Ki Ngo, Ho Yin Edwin Chan, Kwok-Fai Lau
Amyloidogenic processing of APP by β- and γ-secretases leads to the generation of amyloid-β peptide (Aβ), and the accumulation of Aβ in senile plaques is a hallmark of Alzheimer's disease (AD). Understanding the mechanisms of APP processing is therefore paramount. Increasing evidence suggests that APP intracellular domain (AICD) interacting proteins influence APP processing. In this study, we characterized the overexpression of AICD interactor GULP1 in a Drosophila AD model expressing human BACE and APP695...
November 21, 2017: Oncotarget
Jia-Wei Min, Yanying Liu, David Wang, Fangfang Qiao, Hongmin Wang
Tan-67 is a selective non-peptidic δ-opioid receptor (DOR) agonist that confers neuroprotection against cerebral ischemia/reperfusion (I/R)-caused neuronal injury in pre-treated animals. In this study, we examined whether post-ischemic administration of Tan-67 in stroke mice is also neuroprotective and whether the treatment affects expression, maturation and processing of the amyloid precursor protein (APP). A focal cerebral I/R model in mice was induced by middle cerebral artery occlusion for 1 hour (h) and Tan-67 (1...
November 29, 2017: Journal of Neurochemistry
Keiichi Inoue, Luis M A Oliveira, Asa Abeliovich
Mutations in presenilin (PSEN) 1 and 2, which encode components of the γ-secretase (GS) complex, cause familial Alzheimer's disease (FAD). It is hypothesized that altered GS-mediated processing of the amyloid precursor protein (APP) to the Aβ42 fragment, which is accumulated in diseased brain, may be pathogenic. Here, we describe an in vitro model system that enables the facile analysis of neuronal disease mechanisms in non-neuronal patient cells using CRISPR gene activation of endogenous disease-relevant genes...
November 14, 2017: Cell Reports
Karim A Alkadhi, An T Dao
We investigated the effect of treadmill exercise training on the levels of Alzheimer's disease (AD)-related protein molecules in the DG and CA1 areas of a rat model of AD, i.c.v. infusion of Aβ1-42 peptide, 2weeks (250pmol/day). Aβ infusion markedly increased protein levels of amyloid precursor protein (APP), the secretase beta-site APP cleaving enzyme-1 (BACE-1) and Aβ in the CA1 and DG areas. The results also revealed that 4weeks of treadmill exercise prevented the increase in the levels of APP, BACE-1 and Aβ proteins in both hippocampal areas...
January 2018: Molecular and Cellular Neurosciences
Jichao Sun, Subhojit Roy
Alzheimer's disease (AD) is characterized by the accumulation of insoluble deposits of Amyloid β (Aβ) in brains. Aβ is derived by sequential cleavage of the amyloid precursor protein (APP) by β-site secretase enzyme (BACE-1) and γ-secretase. Proteolytic processing of APP by BACE-1 is the rate-limiting step in Aβ production, and this pathway is a prime target for AD drug development. Both APP and BACE-1 are membrane-spanning proteins, transported via secretory and endocytic pathways; and the physical interaction of APP and BACE-1 during trafficking is a key cell biological event initiating the amyloidogenic pathway...
November 6, 2017: Developmental Neurobiology
Luis A Martinez-Alsina, John C Murray, Leanne M Buzon, Mark W Bundesmann, Joseph Michael Young, Brian T O'Neill
We report the diastereoselective synthesis of novel spiropiperidine templates for use in SAR studies of β-secretase (BACE) inhibitors and also as versatile ligands for other receptor types. The overall synthetic approach stems from chiral starting material benzyl (S)-2-methyl-4-oxopiperidine-1-carboxylate and employs an Overman rearrangement to control the stereochemistry at the quaternary center. This process is followed by a Grubbs metathesis to close a 5-membered "top" ring to form an α,β-unsaturated lactam or an α,β-unsaturated sultam...
November 2, 2017: Journal of Organic Chemistry
Stephane Dissel, Markus Klose, Jeff Donlea, Lijuan Cao, Denis English, Raphaelle Winsky-Sommerer, Bruno van Swinderen, Paul J Shaw
To test the hypothesis that sleep can reverse cognitive impairment during Alzheimer's disease, we enhanced sleep in flies either co-expressing human amyloid precursor protein and Beta-secretase (APP:BACE), or in flies expressing human tau. The ubiquitous expression of APP:BACE or human tau disrupted sleep. The sleep deficits could be reversed and sleep could be enhanced when flies were administered the GABA-A agonist 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridine-3-ol (THIP). Expressing APP:BACE disrupted both Short-term memory (STM) and Long-term memory (LTM) as assessed using Aversive Phototaxic Suppression (APS) and courtship conditioning...
January 2017: Neurobiology of Sleep and Circadian Rhythms
Shivani Kumar, Suman Chowdhury, Suresh Kumar
BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace...
October 27, 2017: BMC Neuroscience
Claude-Henry Volmar, Hasib Salah-Uddin, Karolina J Janczura, Paul Halley, Guerline Lambert, Andrew Wodrich, Sivan Manoah, Nidhi H Patel, Gregory C Sartor, Neil Mehta, Nancy T H Miles, Sachi Desse, David Dorcius, Michael D Cameron, Shaun P Brothers, Claes Wahlestedt
Alzheimer's disease (AD) comprises multifactorial ailments for which current therapeutic strategies remain insufficient to broadly address the underlying pathophysiology. Epigenetic gene regulation relies upon multifactorial processes that regulate multiple gene and protein pathways, including those involved in AD. We therefore took an epigenetic approach where a single drug would simultaneously affect the expression of a number of defined AD-related targets. We show that the small-molecule histone deacetylase inhibitor M344 reduces beta-amyloid (Aβ), reduces tau Ser396 phosphorylation, and decreases both β-secretase (BACE) and APOEε4 gene expression...
October 24, 2017: Proceedings of the National Academy of Sciences of the United States of America
Jacques Hugon, François Mouton-Liger, Julien Dumurgier, Claire Paquet
BACKGROUND: Brain lesions in Alzheimer's disease (AD) are characterized by Aβ accumulation, neurofibrillary tangles, and synaptic and neuronal vanishing. According to the amyloid cascade hypothesis, Aβ1-42 oligomers could trigger a neurotoxic cascade with kinase activation that leads to tau phosphorylation and neurodegeneration. Detrimental pathways that are associated with kinase activation could also be linked to the triggering of direct neuronal death, the production of free radicals, and neuroinflammation...
October 5, 2017: Alzheimer's Research & Therapy
Meaghann Weaver, Christopher Wichman, Cheryl Darnall, Sue Bace, Catherine Vail, Andrew MacFadyen
BACKGROUND: One goal of pediatric palliative care is to maintain quality of life for children and their families. Quality-of-life investigations may be enhanced by considering clinically important metrics in addition to statistical significance. OBJECTIVE: The purpose of this study was to longitudinally evaluate the effect of time on quality of life and family impact for pediatric palliative care patients across all diagnoses and ages. DESIGN: This prospective quality-of-life study included administration of a 23-item PedsQL™ Measurement Model to evaluate for physical, emotional, social, and cognitive dimensions of the child's quality of life and a 36-item PedsQL Family Impact Module to assess for the familial impact at time of initial palliative care consultation, Month 6, and Month 12...
September 28, 2017: Journal of Palliative Medicine
Akhil Kumar, Gaurava Srivastava, Ashok Sharma
Due to multifactorial nature of Alzheimer's disease one target-one ligand hypothesis often looks insufficient. BACE-1 and GSK-3β are well established therapeutic drug targets and interaction between BACE-1 and GSK-3β pathways has also been established. Thus, designing of dual inhibitor for these two targets seems rational and may provide effective therapeutic strategies against AD. Recent studies revealed that only two scaffolds i.e. triazinone and curcumin act as a dual inhibitor against BACE-1 and GSK-3β...
September 8, 2017: Computational Biology and Chemistry
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