A5003976467- Pharmacogenetics and Drug Metabolism
- SARS-CoV-2 and COVID-19 Research
- Computational Drug Discovery Methods
- COVID-19 Clinical Research Studies
- Analytical Chemistry and Chromatography
- Drug Transport and Resistance Mechanisms
- Metabolomics and Mass Spectrometry Studies
- Receptor Mechanisms and Signaling
- Glycosylation and Glycoproteins Research
- Protein Interaction Studies and Fluorescence Analysis
- Antibiotics Pharmacokinetics and Efficacy
- Amino Acid Enzymes and Metabolism
- Biochemical and Molecular Research
- Chronic Myeloid Leukemia Treatments
- Acute Lymphoblastic Leukemia research
- Chronic Lymphocytic Leukemia Research
- Influenza Virus Research Studies
- Metabolism, Diabetes, and Cancer
- Viral gastroenteritis research and epidemiology
- Protein purification and stability
- Synthesis and biological activity
- Metabolism and Genetic Disorders
- Vitamin C and Antioxidants Research
- Drug-Induced Hepatotoxicity and Protection
- Microbial Metabolic Engineering and Bioproduction
Pfizer (United States)
2017-2025
University of Manchester
2017-2018
Simcyp (United Kingdom)
2017-2018
University of North Carolina at Chapel Hill
2017
The worldwide outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. Alongside vaccines, antiviral therapeutics are an important part the healthcare response to countering ongoing threat presented COVID-19. Here, we report discovery and characterization PF-07321332, orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human activity excellent off-target selectivity vivo safety profiles. PF-07321332...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor PF-07321332 (nirmatrelvir), in combination with ritonavir (Paxlovid), was recently granted emergency use authorization by multiple regulatory agencies for the treatment of disease 2019 (COVID-19) adults and pediatric patients. Disposition studies on nirmatrelvir animals human reagents, which were used to support clinical studies, are described herein. Plasma clearance moderate rats (27.2 ml/min per...
Despite the record-breaking discovery, development and approval of vaccines antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained fourth leading cause death in world third highest United States 2022. Here, we report discovery characterization PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, component ritonavir-boosted therapy Paxlovid. We demonstrate
In early 2020, severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infections leading to COVID-19 disease reached a global level the World Health Organization (WHO) declaration of pandemic. Scientists around globe rapidly responded try and discover novel therapeutics repurpose extant drugs treat disease. This work describes preclinical discovery efforts that led invention PF-07321332 (nirmatrelvir, 14), potent orally active inhibitor SARS CoV-2 main protease (Mpro) enzyme. At outset...
Quantitative characterization of UDP-glucuronosyltransferase (UGT) enzymes is valuable in glucuronidation reaction phenotyping, predicting metabolic clearance and drug-drug interactions using extrapolation exercises based on pharmacokinetic modeling. Different quantitative proteomic workflows have been employed to quantify UGT various systems, with reports indicating large variability expression, which cannot be explained by interindividual alone. To evaluate the effect methodological...
The worldwide outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome 2 (SARS-CoV-2) has become an established global pandemic. Alongside vaccines, antiviral therapeutics are important part the healthcare response to counter ongoing threat presented COVID-19. Here, we report discovery and characterization PF-07321332, orally bioavailable SARS-CoV-2 main protease inhibitor with in vitro pan-human activity, excellent off-target selectivity vivo safety...
The utility of chemical inhibitors in cytochrome P450 (CYP) reaction phenotyping is highly dependent on their selectivity and potency for target CYP isoforms. In the present study, 17 CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4/5 commonly used were evaluated cross-enzyme pooled human liver microsomes. data using a statistical desirability analysis to identify (1) superior (2) optimal concentrations each. Among evaluated, <i>α</i>-naphthoflavone, furafylline, sulfaphenazole, tienilic acid,...
<s><s></s></s> Brepocitinib is an oral once-daily Janus kinase 1 and Tyrosine 2 selective inhibitor currently in development for the treatment of several autoimmune disorders. Mass balance metabolic profiles were determined using accelerator mass spectrometry six healthy male participants following a single 60 mg dose <sup>14</sup>C-brepocitinib (~300 nCi). The average recovery was 96.7% {plus minus} 6.3% with majority (88.0% 8.0%) recovered urine 8.7% 2.1% feces....
Quantitative proteomic methods require optimization at several stages, including sample preparation, liquid chromatography–tandem mass spectrometry (LC-MS/MS), and data analysis, with the final analysis stage being less widely appreciated by end-users. Previously reported measurement of eight uridine-5′-diphospho-glucuronosyltransferases (UGT) generated two laboratories [using stable isotope-labeled (SIL) peptides or quantitative concatemer (QconCAT)] reflected significant disparity between...
Plasma protein binding (PPB) studies on the SARS-CoV-2 main protease inhibitor nirmatrelvir revealed considerable species differences primarily in dog and rabbit, which prompted further investigations into biochemical basis for these differences.The unbound fraction (fu) of rabbit plasma was concentration (2–200 µM)-dependent (dog fu,p 0.024–0.69, 0.010–0.82). Concentration (0.1–100 serum albumin (SA) (fu,SA 0.040–0.82) alpha-1-acid glycoprotein (AAG) (fu,AAG 0.050–0.64) observed dogs....
Cytochrome P450 reaction phenotyping to determine the fraction of metabolism (f<sub>m</sub>) values for individual enzymes is a standard study in evaluation new drug. However, there are technical challenges these studies caused by shortcomings selectivity inhibitors and unreliable scaling procedures recombinant (rCYP) data. In this investigation, two-step "qualitative-then-quantitative" approach described. first step, each rCYP tested qualitatively potential generate metabolites. second...
The use of intersystem extrapolation factors (ISEF) is required for the quantitative scaling drug metabolism data generated in individually expressed cytochrome P450 (CYP) enzymes when estimating fractional contribution (f<sub>m</sub>) to by vivo. For successful prediction f<sub>m</sub>, ISEF values must be universal across all substrates any individual enzyme. In this study, were ten CYP3A4 selective using a common source recombinant heterologously (rCYP) and pool human liver microsomes....