A5078570045- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Blood Coagulation and Thrombosis Mechanisms
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- RNA modifications and cancer
- Hemophilia Treatment and Research
- Virus-based gene therapy research
- Viral Infectious Diseases and Gene Expression in Insects
- CAR-T cell therapy research
- Lipoproteins and Cardiovascular Health
- Cardiac electrophysiology and arrhythmias
- Blood properties and coagulation
- Monoclonal and Polyclonal Antibodies Research
- Mycotoxins in Agriculture and Food
- Biosimilars and Bioanalytical Methods
- CRISPR and Genetic Engineering
- Atrial Fibrillation Management and Outcomes
- Carcinogens and Genotoxicity Assessment
- Animal testing and alternatives
- Genomics, phytochemicals, and oxidative stress
- Metal complexes synthesis and properties
- Glutathione Transferases and Polymorphisms
- Retinal Development and Disorders
- Mast cells and histamine
Pfizer (United States)
2014-2023
Drug Safety Research Unit
2019
Queen's University
1996-2001
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that compound PF-06446846 inhibits translation PCSK9 by inducing ribosome to stall around codon 34, mediated sequence nascent chain within exit tunnel. We further show reduces and total rats following oral dosing. Using profiling, is highly selective for inhibition translation. The mechanism action employed reveals...
Abstract Targeting of the human ribosome is an unprecedented therapeutic modality with a genome‐wide selectivity challenge. A liver‐targeted drug candidate described that inhibits ribosomal synthesis PCSK9, lipid regulator considered undruggable by small molecules. Key to concept was identification pharmacologically active zwitterions designed be retained in liver. Oral delivery poorly permeable achieved prodrugs susceptible cleavage carboxylesterase 1. The select tetrazole crucial....
A noneffector, active site–dependent human IgG1 specific to factor XIa inhibits thrombus formation in two animal models at clinically relevant doses without a detectable effect on hemostasis.
The optimization of a new class small molecule PCSK9 mRNA translation inhibitors is described. potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions molecule. last step in synthesis congested amide center was enabled three different routes. Subtle structural yielded significant margins. These efforts led identification 7l 7n overall profiles suitable for vivo evaluation. In 14-day toxicology study,...
PF-06438179, a potential biosimilar to Remicade® (infliximab, Janssen Biotech, Inc.), is chimeric mouse–human monoclonal antibody targeting human tumor necrosis factor alpha (TNF). Analytical (small subset reported here) and nonclinical studies compared the structural, functional, in vivo similarity of PF-06438179 with Remicade sourced from United States (infliximab-US) and/or European Union (infliximab-EU). The peptide map profiles were superimposable, masses same, indicating identical...
Amiodarone (AM), a potent antidysrhythmic agent, can cause potentially life-threatening pulmonary fibrosis. In the present investigation of mechanisms initiation AM lung toxicity, we found that 100 microM decreased mitochondrial membrane potential in intact hamster alveolar macrophages and preparations enriched isolated type II cells nonciliated bronchiolar epithelial (Clara) cells, following 2 h incubation. This was followed by drop cellular ATP content (by 32--77%) at 4 to 6 h, 30 55% loss...
Nonclinical development strategies for gene therapies are unique from other modalities. The European Federation of Pharmaceutical Industries and Associates (EFPIA) Gene Therapy Working Group surveyed EFPIA member nonmember pharmaceutical biotechnology companies about their current practices designing implementing nonclinical toxicology studies to support the viral vector-delivered in vivo therapies. Compiled responses 17 indicated that these had some variability species selection,...
Treatment of cardiac dysrhythmias with the iodinated benzofuran derivative amiodarone (AM) is limited by pulmonary toxicity. The susceptibilities different lung cell types male Golden Syrian hamsters to AM-induced cytotoxicity were investigated in vitro. Bronchoalveolar lavage and protease digestion release cells, followed centrifugal elutriation density gradient centrifugation, resulted preparations enriched alveolar macrophages (98%), type II cells (75-85%), nonciliated bronchiolar...
Abstract Targeting of the human ribosome is an unprecedented therapeutic modality with a genome‐wide selectivity challenge. A liver‐targeted drug candidate described that inhibits ribosomal synthesis PCSK9, lipid regulator considered undruggable by small molecules. Key to concept was identification pharmacologically active zwitterions designed be retained in liver. Oral delivery poorly permeable achieved prodrugs susceptible cleavage carboxylesterase 1. The select tetrazole crucial....
A zymogen-like activated factor X variant (FXa I16L ) is being developed for treating acute bleeding conditions. Activated V an essential cofactor to FXa activating prothrombin thrombin. Thrombi/emboli formation was observed microscopically in toxicity studies animals. The objective of this research evaluate candidate biomarkers -induced thrombi/emboli inform safety monitoring and dose-escalation decisions clinical trials. Effects intravenous administration on platelets, fibrinogen, partial...
Abstract Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a key role in regulating the levels of plasma low density lipoprotein cholesterol (LDL-C). Here we demonstrate that compound PF-06446846 inhibits translation PCSK9 by inducing ribosome to stall around codon 34, mediated sequence nascent chain within exit tunnel. We further show reduces and total rats following oral dosing. Using profiling, is highly selective for inhibition translation. The mechanism action employed reveals...
Introduction: Wistar Han rats are a preferred strain of rodents for general toxicology and safety pharmacology studies in drug development. In some these studies, visual functional tests that assess retinal toxicity included as an additional endpoint. Although the influence gender on human function has been documented more than 6 decades, preclinically it is still uncertain if there differences between naïve male female rats. Methods: this study, sex-related were quantified by analyzing...