A5056866147- Alzheimer's disease research and treatments
- Liver Disease Diagnosis and Treatment
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Peroxisome Proliferator-Activated Receptors
- Cholinesterase and Neurodegenerative Diseases
- Diet and metabolism studies
- Diet, Metabolism, and Disease
- Prion Diseases and Protein Misfolding
- Adipose Tissue and Metabolism
- Cancer, Lipids, and Metabolism
- Supramolecular Self-Assembly in Materials
- Metabolism, Diabetes, and Cancer
- Drug Transport and Resistance Mechanisms
- Chemical Synthesis and Analysis
- Lipid metabolism and biosynthesis
- Regulation of Appetite and Obesity
- Diabetes Treatment and Management
- Biochemical Analysis and Sensing Techniques
- Lipid metabolism and disorders
- Chronic Lymphocytic Leukemia Research
- Pharmacology and Obesity Treatment
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Cellular transport and secretion
- Receptor Mechanisms and Signaling
Pfizer (United States)
2014-2025
Bayer (United States)
2007-2016
Harvard University
1995-2006
Brigham and Women's Hospital
2000-2004
University of Cincinnati Medical Center
1999-2002
Los Angeles Medical Center
1996-2000
University of California, Los Angeles
1996-2000
University of Minnesota
1996-2000
University of Cincinnati
1998-2000
Boston University
1996-1999
Amyloid plaques composed of the peptide Aβ are an integral part Alzheimer's disease (AD) pathogenesis. We have modeled process amyloid plaque growth by monitoring deposition soluble onto in AD brain tissue or synthetic fibrils and show that it is mediated two distinct kinetic processes. In first phase, "dock", addition to template fully reversible (dissociation t1/2 ≈ 10 min), while second "lock", deposited becomes irreversibly associated ≫ 1000 min) with a time-dependent manner. The most...
To determine the stability of β-amyloid peptide (Aβ) and glial neuronal changes induced by Aβ in CNS vivo , we made single injections fibrillar (fAβ), soluble (sAβ), or vehicle into rat striatum. Injected fAβ is stable for at least 30 d after injection, whereas sAβ primarily cleared within 1 d. After injection fAβ, microglia phagocytize aggregates, nearby astrocytes form a virtual wall between fAβ-containing surrounding neuropil. Similar are not observed injection. Microglia near injected...
Presenilin heterodimers apparently contain the active site of γ-secretase, a polytopic aspartyl protease involved in transmembrane processing both Notch receptor and amyloid-β precursor protein. Although critical to embryonic development pathogenesis Alzheimer's disease, this is difficult characterize, primarily because it multicomponent complex integral membrane proteins. Here functional γ-secretase was isolated by using an immobilized site-directed inhibitor protease. nicastrin bound...
Ghrelin, through action on its receptor, GH secretagogue receptor type 1a (GHS-R1a), exerts a variety of metabolic functions including stimulation appetite and weight gain suppression insulin secretion. In the present study, we examined effects novel small-molecule GHS-R1a antagonists secretion, glucose tolerance, loss. Ghrelin dose-dependently suppressed secretion from dispersed rat islets. This effect was fully blocked by antagonist. Consistent with this observation, single oral dose...
The peptide hormone ghrelin is the endogenous ligand for type 1a growth secretagogue receptor (GHS-R1a) and only currently known circulating appetite stimulant. GHS-R1a antagonism has therefore been proposed as a potential approach obesity treatment. More recently, recognized to also play role in controlling glucose-induced insulin secretion, which suggests another possible benefit antagonist, namely, an with value diabetes In our laboratories, piperidine-substituted quinazolinone...
Abstract The phosphoinositide 3‐kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or the genetic mutation and amplification of key components. A variety PI3K isoforms play differential roles cancers. As such, development inhibitors from novel compound classes should lead to pharmacological pharmacokinetic profiles allow exploration various indications, combinations, dosing regimens. screening effort...
Recent studies suggest that excess dietary fructose contributes to metabolic dysfunction by promoting insulin resistance, de novo lipogenesis (DNL), and hepatic steatosis, thereby increasing the risk of obesity, type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH), related comorbidities. Whether this is driven calories contained in or whether catabolism itself uniquely pathogenic remains controversial. We sought test a small molecule inhibitor primary metabolizing enzyme...
Alzheimer's disease (AD) is pathologically characterized by the presence of numerous insoluble amyloid plaques in brain composed primarily a 40-43 amino acid peptide, human beta-amyloid peptide (A beta). The process A beta deposition can be modeled vitro physiological concentrations radiolabeled onto preexisting preparations unfixed AD cerebral cortex. Using this model system, it has been shown that biochemically distinct from aggregation and occurs readily at concentrations, but which...
Signaling from the Notch (N) receptor is essential for proper cell-fate determinations and tissue patterning in all metazoans. N signaling requires a presenilin (PS)-dependent transmembrane-cleaving activity that closely related or identical to gamma-secretase proteolysis of amyloid-beta precursor protein (APP) involved Alzheimer's disease pathogenesis. Here, we show N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester, potent inhibitor reported reduce levels transgenic...
Senile plaques composed of the peptide Abeta contribute to pathogenesis Alzheimer's disease (AD), and mechanisms underlying their formation growth may be exploitable as therapeutic targets. To examine process amyloid plaque in human brain, we have utilized size exclusion chromatography (SEC), translational diffusion measured by NMR, vitro models identify oligomerization state that is competent add onto an existing deposit. SEC radiolabeled unlabeled over a concentration range...
Abstract: The major pathological feature of Alzheimer's disease is the presence a high density amyloid plaques in brain tissue patients. are predominantly composed human β‐amyloid peptide (Aβ), 39–43‐mer neurotoxicity which related to its aggregation state. Previous work has demonstrated that certain metals have been implicated as risk factors for (Al, Fe, and Zn) also cause substantial Aβ. In particular, we reported zinc cations at concentrations >10 −4 M dramatically accelerate rate Aβ...
Tumor cell proliferation and migration processes are regulated by multiple metabolic pathways including glycolysis de novo lipogenesis. Since acetyl-CoA carboxylase (ACC) is at the junction of lipids synthesis oxidative pathways, we investigated whether use a dual ACC inhibitor would provide potential therapy against certain lipogenic cancers. The impact ACC1/ACC2 inhibition was using as well siRNA knock down on cellular viability metabolism two glioblastoma multiform cancer lines, U87 more...
Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, identification tool compounds suitable to test hypothesis in human trials has been challenging. An advanced series spirocyclic ketone-containing ACC recently reported by Pfizer were metabolized vivo ketone reduction, which complicated pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated...
Background & AimsDisordered metabolism, steatosis, hepatic inflammation, and fibrosis contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) catalyzes first committed step in de novo lipogenesis (DNL) modulates mitochondrial fatty acid oxidation. Increased DNL flux reduced oxidation are hypothesized steatosis. Some proinflammatory cells also show increased dependency on DNL, suggesting that ACC may regulate aspects inflammatory response NASH....
Abstract PF‐05221304 is a liver‐targeted inhibitor of acetyl‐CoA carboxylase, an enzyme that catalyzes the first committed step in de novo lipogenesis (DNL). This first‐in‐human study investigated safety/tolerability and pharmacokinetics single multiple ascending oral doses, fructose‐stimulated DNL inhibition with repeated doses. Healthy subjects (n = 96) received (1‐240 mg) or (2‐200 mg daily) doses for 14 days 100‐mg without food. was well tolerated at all Repeated inhibited hepatic...
γ-Secretase is an intramembrane-cleaving protease whose substrates include Notch and the amyloid precursor protein (APP). On basis of initial genetic pharmacologic data, γ-secretase activity responsible for cleavage both proteins appears to be identical. However, apparent differences in site sequence specificity raise questions about degree similarity between APP γ-like proteolysis. In effort resolve this issue directly, we established vitro assay that cleaves APP- Notch-based substrates,...
A salient pathological feature of Alzheimer's disease (AD) is the presence amyloid plaques in brains affected patients. The are predominantly composed human β-amyloid peptide (Aβ). Although aggregation synthetic Aβ has been extensively studied, mechanism AD plaque growth poorly understood. In order to address this question, we used an vitro model determine if assembly or required for deposition. Labeled at physiological concentrations readily deposited onto both neuritic and diffuse...
De novo lipogenesis is essential for human sebum production, and increased lipogenic flux accounts excessive production in acne vulgaris.