A5076882415- Alzheimer's disease research and treatments
- Cholinesterase and Neurodegenerative Diseases
- Circadian rhythm and melatonin
- Computational Drug Discovery Methods
- Neuroinflammation and Neurodegeneration Mechanisms
- Drug Transport and Resistance Mechanisms
- Sleep and Wakefulness Research
- Pluripotent Stem Cells Research
- Neurogenesis and neuroplasticity mechanisms
- Prion Diseases and Protein Misfolding
- Sleep and related disorders
- Neuroscience and Neuropharmacology Research
- Genetics, Aging, and Longevity in Model Organisms
- RNA Research and Splicing
- Biochemical effects in animals
- Dementia and Cognitive Impairment Research
- Lipid Membrane Structure and Behavior
- 14-3-3 protein interactions
- Phosphodiesterase function and regulation
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Metabolism and Genetic Disorders
- Neurobiology and Insect Physiology Research
- Pharmacogenetics and Drug Metabolism
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Neurological Complications and Syndromes
Akebia Therapeutics (United States)
2019
Pfizer (United States)
2006-2012
Harvard University
1992-2007
Boston Children's Hospital
2002-2007
Nathan Kline Institute for Psychiatric Research
2006
New York University
2006
Children's Hospital
2001
Boston Children's Museum
2001
Harvard University Press
2000
Brown University
1993-1999
The "long nights" protocol was designed to evaluate sleep processes and circadian rhythm parameters in young humans. A total of 19 children (10 boys, ages 11.2 14.1 years [mean = 12.7 ± 1.0], 9 girls, 12.2 14.4 13.1 0.7]) took part the study. Sleep/wake initially assessed at home using actigraphy diary for 1 week on each child's self-selected sched ule followed by an 8-night fixed light-dark (LD) condition, while sleeping from 22:00 08:00 h wearing eye mask exclude as much light possible....
Sleep disruption and other circadian rhythm disturbances are frequently seen in dementia patients. In this study, we examined the suprachiasmatic nucleus (SCN), putative site of hypothalamic pacemaker, to determine nature degree pathologic changes caused by severe dementia. Neuropathologic examination indicated that among 30 patients with a clinical history dementia, 22 had Braak stage V0VI Alzheimer disease, 3 combined Parkinson Pick disease 2 hippocampal sclerosis. Comparisons were made...
Casein kinase Iϵ (CKIϵ) is an essential component of the biological clock, phosphorylating PER proteins, and in doing so regulating their turnover nuclear entry oscillator cells suprachiasmatic nucleus (SCN). Although hereditary decreases phosphorylation have been well characterized, little known about consequences acute enzyme inhibition by pharmacological means. A novel reagent, 4-[3-cyclohexyl-5-(4-fluoro-phenyl)-3<i>H</i>-imidazol-4-yl]-pyrimidin-2-ylamine (PF-670462), proved to be both...
LY-450139 is a γ-secretase inhibitor shown to have efficacy in multiple cellular and animal models. Paradoxically, robust elevations of plasma amyloid-β (Aβ) been reported dogs humans after administration subefficacious doses. The present study sought further evaluate Aβ responses the guinea pig, nontransgenic model that has an sequence identical human. Male pigs were treated with (0.2–60 mg/kg), brain, cerebrospinal fluid, levels characterized at 1, 3, 6, 9, 14 h postdose. Low doses...
Abstract Neuroinflammation is a key driver of neurodegenerative disease, however the tools available to model this disease biology at systems level are lacking. We describe translational drug discovery platform based on organotypic culture murine cortical brain slices that recapitulate disease-relevant neuroinflammatory biology. After an acute injury response, assume chronic state marked by transcriptomic profiles indicative activation microglia and astrocytes loss neuronal function....
PF-3084014 [(<i>S</i>)-2-((<i>S</i>)-5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-<i>N</i>-(1-(2-methyl-1-(neopentylamino)propan-2-yl)-1<i>H</i>-imidazol-4-yl)pentanamide] is a novel γ-secretase inhibitor that reduces amyloid-β (Aβ) production with an in vitro IC<sub>50</sub> of 1.2 nM (whole-cell assay) to 6.2 (cell-free assay). This compound inhibits Notch-related T- and B-cell maturation thymocyte assay EC<sub>50</sub> 2.1 μM. A single acute dose showed dose-dependent reduction...
A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position natural product was replaced with either carbamates or ethers to provide compounds better metabolic stability. With one those pharmacophores in place C24, morpholines were installed C3 refine physicochemical properties analogues. This strategy gave low clearance and good distribution into central nervous system (CNS) CD-1 mice. Two these compounds, 100 120, tested for a pharmacodynamic...
Purpose. The underlying pathophysiology contributing to coronary heart disease also predisposes patients cerebrovascular and associated cognitive disorders. Although prior studies have focused on the neuropsychological sequelae of specific cardiac problems, few examined capacities limitations typical patients. current study was designed examine functioning among a sample rehabilitation (CR) Methods. Using instruments, were compared in CR program age-matched outpatient control subjects who...
Phosphodiesterase 5A (PDE5A) inhibitors improve functional recovery after middle cerebral artery occlusion (MCA-o) in rats. We used the PDE5A inhibitor 3-(4-(2-hydroxyethyl)piperazin-1-yl)-7-(6-methoxypyridin-3-yl)-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1<i>H</i>)-one hydrochloride (PF-5) to determine timing, duration, and degree of inhibition that yields maximum efficacy. also investigated localization tissues cells would be targets for PDE5 may mediate Nearly complete PDE5A, starting 24...
Alzheimer disease patients exhibit irregularities in the patterns of normally circadian (daily) rhythms. Alzheimer-type pathology has been reported hypothalamus and suprachiasmatic nuclei, putative site oscillator. We examined relationship between neuropathology disease, as modeled by an animal system, dysregulation grafting genetically transformed cells that overexpress beta/A4 amyloid into nuclei adult rats. Grafts beta/A4-positive cells, but not control significantly altered pattern...
Membrane-bound endosomal vesicles play an integral role in multiple cellular events, including protein processing and turnover, often critically regulate the cell-surface availability of receptors other plasma membrane proteins many different cell types. Neurons are no exception, being dependent on function for housekeeping synaptic events. Growing evidence suggests a link between neuronal Alzheimer's disease (AD) pathophysiology. Endosomal abnormalities invariably occur within neurons AD...
The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)—formation amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline—are triggered by A β peptide dysregulation (Kakuda et al., 2006, Sato 2003, Qi-Takahara 2005). Since γ -secretase is critical for production, many in biopharmaceutical community focused on as a target therapeutic approaches disease. However, pharmacological to control activity are...
Modulation of the gamma-secretase enzyme, which reduces production amyloidogenic Aβ42 peptide while sparing other Aβ species, is a promising therapeutic approach for treatment Alzheimer's disease. Satori has identified unique class small molecule modulators (GSMs) capable decreasing levels in cellular and rodent model systems. The compound exhibits potency nM range vitro selective lowering Aβ38 Aβ40 total levels. In vivo, from series, SPI-1865, demonstrates similar pharmacology wild-type CD1...
The discovery of a new series γ-secretase modulators is disclosed. Starting from triterpene glycoside modulator that gave very low brain-to-plasma ratio, initial SAR and optimization involved replacement pendant sugar with morpholines. This modification led to two compounds significantly improved central nervous system (CNS) exposure.
β-Amyloid peptides, tentatively regarded as the principal neurotoxins responsible for Alzheimer9s Disease, make up a set of products that varies significantly among different biological systems. The full implications this complexity and its variations have yet to be defined. In work, Aβ peptide populations were extracted from animal brain tissue or cell-conditioned media, immunoprecipitated with specific antibodies, analyzed by matrix-assisted laser desorption time-of-flight mass...