A5021222547- Chemical Reactions and Isotopes
- Amino Acid Enzymes and Metabolism
- Radiopharmaceutical Chemistry and Applications
- Chemical Synthesis and Analysis
- Asymmetric Hydrogenation and Catalysis
- Synthesis and Biological Evaluation
- Medical Imaging Techniques and Applications
- Mass Spectrometry Techniques and Applications
- Coordination Chemistry and Organometallics
- Receptor Mechanisms and Signaling
- Computational Drug Discovery Methods
- Pharmacogenetics and Drug Metabolism
- Muon and positron interactions and applications
- Synthesis and biological activity
- Neuroscience and Neuropharmacology Research
- Cancer therapeutics and mechanisms
- Crystallization and Solubility Studies
- Melanoma and MAPK Pathways
- X-ray Diffraction in Crystallography
- Neuropeptides and Animal Physiology
- Chemical Synthesis and Characterization
- Fluorine in Organic Chemistry
- Alzheimer's disease research and treatments
- Ginkgo biloba and Cashew Applications
- Epigenetics and DNA Methylation
RTI International
2019-2022
Merck & Co., Inc., Rahway, NJ, USA (United States)
2012-2022
Drug Discovery Laboratory (Norway)
2016
Merck (France)
2016
University of Surrey
1990-2011
Plough Foundation
2010
Institute of Medicinal Plant Development
2006
Pennsylvania State University
1991-1995
Stellenbosch University
1995
Shell (Netherlands)
1988
Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently selectively install deuterium (D) tritium (T) at α-amino sp
Cleavage of the hepatitis C virus (HCV) polyprotein by viral NS3 protease releases functional proteins essential for replication. Recent studies Foy and coworkers strongly suggest that NS3-mediated cleavage host factors may abrogate cellular response to alpha interferon (IFN-alpha) (E. Foy, K. Li, R. Sumpter, Jr., Y.-M. Loo, C. L. Johnson, Wang, P. M. Fish, Yoneyama, T. Fujita, S. Lemon, Gale, Proc. Natl. Acad. Sci. USA 102:2986-2991, 2005, E. Ikeda, Science 300:1145-1148, 2003). Blockage...
A PET tracer is desired to help guide the discovery and development of disease-modifying therapeutics for neurodegenerative diseases characterized by neurofibrillary tangles (NFTs), predominant tau pathology in Alzheimer disease (AD). We describe preclinical characterization NFT 18F-MK-6240.In vitro binding studies were conducted with 3H-MK-6240 tissue slices homogenates from cognitively normal AD human brain donors evaluate affinity selectivity NFTs. Immunohistochemistry phosphorylated was...
Methods to incorporate deuterium and tritium atoms into organic molecules are valuable for medicinal chemistry. The prevalence of pyridines diazines in pharmaceuticals means that new ways label these heterocycles will present opportunities drug design facilitate absorption, distribution, metabolism, excretion (ADME) studies. A broadly applicable protocol is presented wherein pyridines, diazines, converted heterocyclic phosphonium salts then isotopically labeled. isotopes incorporated high...
Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark several neurodegenerative diseases including Alzheimer's disease. In vivo detection NFTs using PET imaging represents a unique opportunity to develop pharmacodynamic tool accelerate discovery new disease modifying therapeutics targeting pathology. Herein, we present 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), novel tracer for...
The synthesis and spectroscopic characterization of a family Ni–X (X = Cl, Br, I, H) complexes supported by the bulky α-diimine chelate N,N′-bis(1R,2R,3R,5S)-(−)-isopinocampheyl-2,3-butanediimine (ipcADI) are described. Diimine-supported, three-coordinate nickel(I)–X have been proposed as key intermediates in host catalytic transformations such C–C C–heteroatom cross-coupling C–H functionalization but until now remained synthetically elusive. A combination structural, spectroscopic,...
Abstract Deuterium exchange labelling using [Ir(COD)(Cy 3 P)(Py)]PF 6 as catalyst and deuterium gas was studied on a number of substituted acetanilides. In most cases products containing ortho to the anilide group were obtained with high degree enrichment. With one exception no evidence for meta , para or methyl seen. The also effective in deuteration acetophenone, benzophenone β‐lactam compound Sch 48461.
In neutrophils, growth-related protein-α (CXCL1) and interleukin-8 (CXCL8), are potent chemoattractants (<i>Cytokine</i><b>14:</b>27–36, 2001; <i>Biochemistry</i><b>42:</b>2874–2886, 2003) can stimulate myeloperoxidase release via activation of the G protein-coupled receptors CXCR1 CXCR2. The role CXCR2 in pathogenesis inflammatory responses has encouraged development small molecule antagonists for these receptors. data presented herein describe pharmacology...
A nickel-catalyzed method for the site-selective hydrogen isotope exchange (HIE) of C(sp2)–H bonds in nitrogen heteroarenes is described and applied to tritiation pharmaceuticals. The α-diimine nickel hydride complex [(iPrDI)Ni(μ2–H)]2 (iPrDI = N,N′-bis(2,6-diisopropylphenyl)-2,3-butanediimine) mediates efficient HIE when employed as a single component precatalyst or generated situ from readily available air-stable metal ligand precursors (iPrDI, [(NEt3)Ni(OPiv)2]2 (Piv pivaloyl) (EtO)3SiH)....
Molecular interactions between the active pharmaceutical ingredient and polymer have potentially substantial impacts on physical stability of amorphous solid dispersions (ASDs), presumably by manipulating molecular mobility miscibility. However, structural details for understanding nature contacts mechanistic roles in various physicochemical thermodynamic events often remain unclear. This study provides a spectroscopic characterization posaconazole (POSA) formulations, second-generation...
Determination of the pharmacokinetics and absolute bioavailability an experimental compound, SCH 900518, following a 89.7 nCi (100 μg) intravenous (iv) dose (14)C-SCH 900518 2 h post 200 mg oral administration nonradiolabeled to six healthy male subjects has been described. The plasma concentration was measured using validated LC-MS/MS system, accelerator mass spectrometry (AMS) used for quantitative determination. Calibration standards quality controls were included every batch sample...
The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development CNS directed therapeutics. We others have investigated muscarinic acetylcholine 4 (M4) positive allosteric modulators (PAMs) for the treatment symptoms associated with neuropsychiatric disorders. In this article, we describe synthesis, vitro, vivo characterization a series central pyridine-related M4 PAMs that can be conveniently radiolabeled...
A physical method is described for the rapid isolation of plant trichomes, with emphasis on stalked glandular types. The technique involved breaking frozen trichomes powdered dry ice and collection heads by sieving from larger tissue fragments. This was applied to several plants that bear similar trichomes: geranium (Pelargonium), potato (Solanum tuberosum), tomato (Lycopersicon esculentum), squash (Cucurbita pepo), velvetleaf (Abutilon theophrasti). preparation sufficient quality without...
The emergence and evolution of new immunological cancer therapies has sparked a rapidly growing interest in discovering novel pathways to treat cancer. Toward this aim, series pyrrolidine derivatives (compound 5) were identified as potent inhibitors ERK1/2 with excellent kinase selectivity dual mechanism action but suffered from poor pharmacokinetics (PK). challenge PK was overcome by the discovery 3(S)-thiomethyl analog 7. Lead optimization through focused structure–activity relationship...
ABSTRACT Evernimicin (SCH 27899) is a new antibiotic with activity against wide spectrum of gram-positive bacteria and some gram-negative bacteria. Previous metabolic labeling studies indicated that evernimicin specifically inhibited protein synthesis in Staphylococcus aureus . Using susceptible Escherichia coli strain, we demonstrated also E. In cell-free translation assays extracts from either or S. , had 50% inhibitory concentration approximately 125 nM. contrast, systems derived wheat...
A thrombin receptor-radioligand binding assay was developed using [<sup>3</sup>H]A(pF-F)R(ChA)(hR)Y-NH<sub>2</sub>([<sup>3</sup>H]haTRAP), a high affinity receptor-activating peptide (TRAP), and human platelet membranes. Scatchard analysis of saturation data indicated that [<sup>3</sup>H]haTRAP bound to membranes with a<i>K</i><sub><i>d</i></sub> 15 nm <i>B</i><sub>max</sub> 5.2 pmol/mg protein. The reduced by GPPNHP, nonmetabolizable GTP analogue. Various TRAPs TRAP antagonist, but not...
Abstract Metal‐catalysed hydrogen isotope exchange has been widely used in the preparation of deuterium‐ and tritium‐labelled compounds. This review details development utility homogeneous heterogeneous rhodium ruthenium catalysts for compounds by methodology. Copyright © 2010 John Wiley & Sons, Ltd.
Abstract Metal‐catalysed exchange with tritiated water and tritium gas has been extensively used to prepare a wide range of tritium‐labelled compounds in support pharmaceutical research. Examples the utility both heterogeneous homogeneous metal catalysts label very broad structures will be discussed this review. Copyright © 2010 John Wiley & Sons, Ltd.