A5053597191- Pharmacogenetics and Drug Metabolism
- Drug Transport and Resistance Mechanisms
- Computational Drug Discovery Methods
- Analytical Chemistry and Chromatography
- Genomics, phytochemicals, and oxidative stress
- Algal biology and biofuel production
- Carcinogens and Genotoxicity Assessment
- Lipid metabolism and biosynthesis
- Photosynthetic Processes and Mechanisms
- Metabolism and Genetic Disorders
- Biochemical and Molecular Research
- Axial and Atropisomeric Chirality Synthesis
- Metabolomics and Mass Spectrometry Studies
- Pancreatic function and diabetes
- Diet, Metabolism, and Disease
- Liver Disease Diagnosis and Treatment
- Receptor Mechanisms and Signaling
- Phosphodiesterase function and regulation
- Protist diversity and phylogeny
- Endoplasmic Reticulum Stress and Disease
- Diabetes Treatment and Management
- Pharmacological Effects and Toxicity Studies
- Statistical Methods in Clinical Trials
- Neuroscience and Neuropharmacology Research
- X-ray Diffraction in Crystallography
Pfizer (United States)
2013-2025
Center for Cancer Research
2005-2010
National Cancer Institute
2005-2010
Arizona State University
2010
University of Hawaii System
2005-2006
Aldehyde oxidase (AO) metabolism could lead to significant underestimation of clearance in prediction human pharmacokinetics as well unanticipated exposure AO-generated metabolites, if not accounted for early drug research. We report a method using cryopreserved hepatocytes and the time-dependent AO inhibitor hydralazine (K(I) = 83 ± 27 μM, k(inact) 0.063 0.007 min(-1)), which estimates contribution relative total hepatic clearance. Using zaleplon probe substrate simultaneously monitoring...
In vitro–in vivo correlation (IVIVC) of intrinsic clearance in preclinical species rat and dog was established using the hepatocyte relay method to support high-confidence prediction human pharmacokinetics for low-clearance compounds. Good IVIVC observed most compounds, with predicted values within 2-fold values. The exceptions involved transporter-mediated uptake or metabolizing enzymes extensive extrahepatic contribution. This is first assay available address low challenges drug discovery....
The discovery of D1 subtype-selective agonists with drug-like properties has been an enduring challenge for the greater part 40 years. All known D1-selective are catecholamines that bring about receptor desensitization and undergo rapid metabolism, thus limiting their utility as a therapeutic chronic illness such schizophrenia Parkinson's disease. Our high-throughput screening efforts on yielded single non-catecholamine hit PF-4211 (6) was developed into series potent agonist leads high oral...
Accurate prediction of human pharmacokinetics (PK) remains one the key objectives drug metabolism and PK (DMPK) scientists in discovery projects. This is typically performed by using vitro-in vivo extrapolation (IVIVE) based on mechanistic models. In recent years, machine learning (ML), with its ability to harness patterns from previous outcomes predict future events, has gained increased popularity application absorption, distribution, metabolism, excretion (ADME) sciences. study compares...
Summary In the filamentous cyanobacterium Anabaena sp. PCC 7120 patS and hetN suppress differentiation of vegetative cells into nitrogen‐fixing heterocysts to establish maintain a pattern single separated by approximately 10 undifferentiated cells. Here we show that ‐ ‐dependent suppression pathways are only major factors prevent from differentiating when source ammonia is not present. The independent each other, inactivation both leads almost all filament in absence fixed nitrogen, compared...
Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for treatment non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is first-in-class DGAT2 addressed potential development risks prototype liver-targeted PF-06427878. Key design elements culminated in discovery (1) replacement metabolically labile motif 3,5-disubstituted...
The hetR, patA, hetN, and patS genes are part of a regulatory network that regulates the differentiation patterning heterocysts in filamentous cyanobacterium Anabaena sp. strain PCC 7120. In this report, epistatic interactions mutant alleles these four have been used to refine our understanding their relationships one another. hetR gene was necessary for genetic backgrounds normally give rise excessive differentiation, supporting its role as master regulator indicating HetR directly factors...
We disclose the discovery and X-ray cocrystal data of potent, selective quinazoline inhibitors PDE1. Inhibitor ( S)-3 readily attains free plasma concentrations above PDE1 IC50 values has restricted brain access. The racemic compound 3 inhibits >75% PDE hydrolytic activity in soluble samples human myocardium, consistent with heightened this tissue. These compounds represent promising new tools to probe value inhibition treatment cardiovascular disease.
Ertugliflozin is primarily cleared through UDP-glucurosyltransferase (UGT)–mediated metabolism (86%) with minor oxidative clearance (12%). In vitro phenotyping involved enzyme kinetic characterization of UGTs or cytochrome P450 enzymes catalyzing formation the major 3-<i>O</i>-<i>β</i>-glucuronide (M5c) and 2-<i>O</i>-<i>β</i>-glucuronide (M5a), monohydroxylated ertugliflozin (M1 M3), des-ethyl (M2) metabolites in human liver microsomes (HLMs). Fractional (f<sub>CL</sub>) from HLM intrinsic...
Inhibition of branched-chain ketoacid dehydrogenase kinase (BDK or BCKDK), a negative regulator amino acid (BCAA) metabolism, is hypothesized to treat cardio-metabolic diseases. From starting point with potential idiosyncratic toxicity risk, modification benzothiophene core and discovery cryptic pocket allowed for improved potency 3-aryl substitution arrive at PF-07328948, which was largely devoid protein covalent binding liability. This BDK inhibitor shown also be degrader in cells vivo...
The prediction of human drug metabolites using in vitro experiments containing human-derived reagents is an important approach modern research; however, this can be challenging for drugs that are slowly metabolized. In report, we describe the use a recently developed hepatocyte relay method purpose predicting metabolite profiles. Five compounds which vivo metabolism data were available selected investigation method, and results compared with gathered suspensions as well previous from...
Drug interactions involving the inhibition of hepatic organic anion transporting polypeptides (OATPs) 1B1 and OATP1B3 are considered important. Therefore, we sought to study various sulfated bile acids (BA-S) as potential clinical OATP1B1/3 biomarkers. It was determined that BA-S [e.g., glycochenodeoxycholic acid 3-O-sulfate (GCDCA-S) glycodeoxycholic (GDCA-S)] substrates OATP1B1, OATP1B3, sodium-dependent taurocholic cotransporting polypeptide (NTCP) transfected into human embryonic kidney...
6-Chloro-5-[4-(1-hydroxycyclobutyl)phenyl]-1<i>H</i>-indole-3-carboxylic acid (PF-06409577) is a direct activator of the human <i>β</i>1-containing adenosine monophosphate-activated protein kinase (ΑMPK) isoforms. The clearance mechanism PF-06409577 in animals and humans involves uridine diphosphoglucuronosyl transferase (UGT)–mediated glucuronidation to an acyl glucuronide metabolite...
Diacylglycerol O-acyltransferase 2 (DGAT2) inhibitors have been shown to lower liver triglyceride content and are being explored clinically as a treatment for non-alcoholic steatohepatitis (NASH). This work details efforts find an extended-half-life DGAT2 inhibitor. A basic moiety was added known inhibitor template, the basicity lipophilicity were fine-tuned by addition of electrophilic fluorines. weakly profile required appropriate balance potency, clearance, permeability. culminated in...
ABSTRACT In recent decades advances in radiation imaging and therapy have led to a dramatic increase the number of people exposed radiation. Consequently, there is clear need for personalized biodosimetry diagnostics order monitor dose received adapt it each patient depending on their sensitivity exposure (Hall Brenner Citation2008). Similarly, after large-scale radiological event such as dirty bomb attack, will be major assess, within few days, doses by tens thousands individuals. Current...