A5090226793- Phytoestrogen effects and research
- HIV/AIDS drug development and treatment
- Biosimilars and Bioanalytical Methods
- Hepatitis C virus research
- Nutritional Studies and Diet
- Neuroscience and Neuropharmacology Research
- Microfluidic and Capillary Electrophoresis Applications
- Neurotransmitter Receptor Influence on Behavior
- Fatty Acid Research and Health
- Eicosanoids and Hypertension Pharmacology
- Monoclonal and Polyclonal Antibodies Research
- Diet and metabolism studies
- Colorectal Cancer Screening and Detection
- Genetic factors in colorectal cancer
- Advanced Biosensing Techniques and Applications
- Bipolar Disorder and Treatment
- Biosensors and Analytical Detection
- Cancer, Hypoxia, and Metabolism
- Microfluidic and Bio-sensing Technologies
- Mass Spectrometry Techniques and Applications
- RNA modifications and cancer
- Hepatitis B Virus Studies
- Natural Antidiabetic Agents Studies
- Cancer Risks and Factors
- Diet, Metabolism, and Disease
Neurocrine Biosciences (United States)
2017-2025
Pfizer (United States)
2007-2012
Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa
2003
Fred Hutch Cancer Center
2002
The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report optimization dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led discovery 24 (PF-00868554). Compound is a potent selective inhibitor with favorable pharmacokinetic profile recently entered phase II clinical evaluation in patients genotype 1 HCV.
PF-00868554 is a nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase, which exerts its inhibitory effect by binding to thumb base domain protein. It potent and selective inhibitor, with mean 50% concentration 0.019 microM against genotype 1 polymerases effective (EC(50)) 0.075 1b-Con1 replicon. To determine in vitro antiviral activity various HCV strains, panel chimeric replicons was generated, polymerase sequences derived from 1a 1b clinical isolates were cloned into...
Initial pharmacokinetic (PK) studies of discovery compounds are conducted in mice to demonstrate exposure prior conducting efficacy studies. PK information obtained from a single mouse by serial blood microsampling, dried spot collection and analyses using microbore (1 mm internal diameter column) LC-MS/MS is presented. Ex vivo plasma concentration ratios (BPRs) were compared with vitro BPRs for 15 compounds.Two orally dosed was collected at time points via sampling. The calculated...
Colorectal cancer (CRC) testing programs reduce mortality; however, approximately 40% of the recommended population who should undergo CRC does not. Early colon detection in patient populations ineligible for testing, such as elderly or those with significant comorbidities, could have clinical benefit. Despite many attempts to identify individual protein markers this disease, little progress has been made. Targeted mass spectrometry, using multiple reaction monitoring (MRM) technology,...
Tetrabenazine (TBZ) activity is thought to result from four isomeric dihydrotetrabenazine (HTBZ) metabolites ([+]-α-HTBZ, [−]-α-HTBZ, [+]-β-HTBZ, [−]-β-HTBZ). Each isomer has a unique profile of vesicular monoamine transporter 2 (VMAT2) inhibition and off-target binding. Previously published data only report total (α) (β) concentrations. We developed method quantify the individual HTBZ isomers in samples patients with Huntington's disease receiving TBZ. For comparison, concentrations...
The discovery and optimization of a novel class carbon-linked dihydropyrones as allosteric HCV NS5B polymerase inhibitors are presented. Replacement the sulfur linker atom with carbon reduced compound acidity greatly increased cell permeation. Further structure-activity relationship (SAR) studies led to identification compounds, exemplified by 23 24, significantly improved antiviral activities in cell-based replicon assay favorable pharmacokinetic profiles.