A5038722159- Pharmacogenetics and Drug Metabolism
- Analytical Chemistry and Chromatography
- Drug Transport and Resistance Mechanisms
- Metabolomics and Mass Spectrometry Studies
- Computational Drug Discovery Methods
- Advanced NMR Techniques and Applications
- Drug-Induced Hepatotoxicity and Protection
- HIV/AIDS drug development and treatment
- Pharmacological Effects and Toxicity Studies
- Neuroscience and Neuropharmacology Research
- Synthesis and Catalytic Reactions
- PI3K/AKT/mTOR signaling in cancer
- Receptor Mechanisms and Signaling
- Molecular spectroscopy and chirality
- NMR spectroscopy and applications
- Colorectal Cancer Treatments and Studies
- Pharmacological Receptor Mechanisms and Effects
- Cancer therapeutics and mechanisms
- Spectroscopy and Quantum Chemical Studies
- Lung Cancer Treatments and Mutations
- Phosphodiesterase function and regulation
- Eicosanoids and Hypertension Pharmacology
- Gastrointestinal motility and disorders
- Diet and metabolism studies
- Electron Spin Resonance Studies
Pfizer (United States)
2014-2024
Biogen (United States)
2024
Netherlands Organisation for Applied Scientific Research
2018
WuXi AppTec (China)
2017
Nebraska Medical Center
2017
University of Nebraska Medical Center
2017
American Cancer Society
2014
Repligen (United States)
2013
Scripps Research Institute
2013
Dartmouth College
2013
Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy can result from silencing of enzymatic activity until protein resynthesis occur, along with potential increased selectivity targeting uniquely positioned nucleophilic residues protein. However, covalent approaches carry additional risk toxicities or hypersensitivity reactions modification unintended targets. Here we describe methods measuring reactivity reactive groups (CRGs) a biologically...
Tofacitinib is a novel, oral Janus kinase inhibitor. The objectives of this study were to summarize the pharmacokinetics and metabolism tofacitinib in humans, including clearance mechanisms. Following administration single 50-mg <sup>14</sup>C-labeled dose healthy male subjects, mean (standard deviation) total percentage administered radioactive recovered was 93.9% (±3.6), with 80.1% (±3.6) urine (28.8% parent), 13.8% (±1.9) feces (0.9% parent). rapidly absorbed, plasma concentrations...
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...
The replacement of one chemical motif with another that is broadly similar a common method in medicinal chemistry to modulate the physical and biological properties molecule (i.e., bioisosterism). In recent years, bioisosteres such as cubane bicyclo[1.1.1]pentane (BCP) have been used highly effective phenyl mimics. Herein, we show successful incorporation range during open-source optimization an antimalarial series. Cubane (19) closo-carborane (23) analogues exhibited improved vitro potency...
Sudoxicam and meloxicam are nonsteroidal anti-inflammatory drugs (NSAIDs) from the enol-carboxamide class. While only structural difference between two NSAIDs is presence of a methyl group on C5-position 2-carboxamidothiazole motif in meloxicam, marked their toxicological profile humans has been discerned. In clinical trials, sudoxicam was associated with several cases severe hepatotoxicity that led to its discontinuation, while market for over decade devoid hepatotoxicity. an attempt...
Acyl-CoA:diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final committed step in biosynthesis of triglycerides. DGAT-1 knockout mice have been shown to be resistant diet-induced obesity and increased insulin sensitivity. Thus, inhibition may represent an attractive target for treatment or type II diabetes. Herein, we report discovery characterization a potent selective inhibitor PF-04620110 (3). Compound 3 inhibits with IC50 19 nM shows high selectivity versus broad panel off-target...
CYP2J2, an arachidonic acid epoxygenase, is recognized for its role in the first-pass metabolism of astemizole and ebastine. To fully assess CYP2J2 drug metabolism, a selective substrate potent specific chemical inhibitor are essential. In this study, we report amiodarone 4-hydoxylation as CYP2J2-catalyzed reaction with no CYP3A4, or other drug-metabolizing enzyme, involvement. Amiodarone 4-hydroxylation enabled determination liver relative activity factor intersystem extrapolation CYP2J2....
CYP3cide (PF-4981517; 1-methyl-3-[1-methyl-5-(4-methylphenyl)-1<i>H</i>-pyrazol-4-yl]-4-[(3<i>S</i>)-3-piperidin-1-ylpyrrolidin-1-yl]-1<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidine) is a potent, efficient, and specific time-dependent inactivator of human CYP3A4. When investigating its inhibitory properties, an extreme metabolic inactivation efficiency (<i>k</i><sub>inact</sub>/<i>K</i><sub>I</sub>) 3300 to 3800 ml · min<sup>−1</sup> μmol<sup>−1</sup> was observed using liver microsomes from...
The contribution of drug metabolites to the pharmacologic and toxicologic activity a can be important; however, for variety reasons frequently difficult synthesize. To meet need having samples further study, we have developed biosynthetic methods coupled with quantitative NMR spectroscopy (qNMR) generate solutions known structure concentration. These used in ways when synthetic sample is unavailable, including assays, standards vitro work help establish clearance pathways, and/or as...
1. Crizotinib (XALKORI®), an oral inhibitor of anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition factor (c-Met), is currently approved for the treatment patients with non-small cell lung cancer that ALK-positive.2. The metabolism, excretion pharmacokinetics crizotinib were investigated following administration a single dose 250 mg/100 µCi [14C]crizotinib to six healthy male subjects.3. Mean recovery [14C]crizotinib-related radioactivity in excreta samples was 85% (63%...
Acyl glucuronides have been implicated in the toxicity of many xenobiotics and marketed drugs. These toxicities are hypothesized to be a consequence covalent binding reactive forms acyl glucuronide proteins. Reactive intermediates arise from migration aglycone leading other positional stereoisomers under physiological conditions. In order screen for potential liabilities these metabolites during early phase pharmaceutical development, an NMR method based on disappearance anomeric resonance...
In discovery and development, having a qualified metabolite standard is advantageous. Chemical synthesis of standards often difficult expensive. As an alternative, biological generation isolation metabolites in the nanomole range are readily feasible. However, without accurately defined concentration, these isolates have limited utility as standards. There significant history NMR both qualitative quantitative technique, concepts been merged recently to provide structural information on...
Enzalutamide and apalutamide are two androgen receptor inhibitors approved for the treatment of castration-resistant prostate cancer (CRPC) nonmetastatic (nmCRPC), respectively. Apalutamide is associated with an increased incidence skin rash above placebo groups in SPARTAN trial nmCRPC TITAN metastatic castration-sensitive patients. On contrary, rate across all clinical trials (including PROSPER [nmCRPC]) enzalutamide similar to placebo. We hypothesized that apalutamide-associated patients...
At one time, biotransformation was a descriptive activity in pharmaceutical development, viewed simply as structural elucidation of drug metabolites, completed only once compounds entered clinical development. Herein, we present our strategic approach using to enable chemistry design/SAR The considers four questions that often themselves medicinal chemists optimizing their for candidate selection: (1) What are the important clearance mechanisms mediate disposition my molecule? (2) Can...
Abrocitinib is an oral once-daily Janus kinase 1 selective inhibitor being developed for the treatment of moderate-to-severe atopic dermatitis. This study examined disposition abrocitinib in male participants following and intravenous administration using accelerator mass spectroscopy methodology to estimate pharmacokinetic parameters characterize metabolite (M) profiles. The results indicated had a systemic clearance 64.2 L/h, steady-state volume distribution 100 L, extent absorption...
Typically human absorption, distribution, metabolism, and excretion (ADME) studies are executed using radiolabeled (e.g., carbon‐14) material, the synthesis of which is a time‐consuming activity. In this study, we were able to assess metabolism unlabeled nirmatrelvir (PF‐07321332) within first‐in‐human study via novel application quantitative fluorine ( 19 F) nuclear magnetic resonance (NMR) spectroscopy in place standard radiolabel ADME study. Six healthy participants received single 300‐mg...
In the search for novel bile acid (BA) biomarkers of liver organic anion-transporting polypeptides (OATPs), cynomolgus monkeys received oral rifampicin (RIF) at four dose levels (1, 3, 10, and 30 mg/kg) that generated plasma-free <i>C</i><sub>max</sub> values (0.06, 0.66, 2.57, 7.79 <i>µ</i>M, respectively) spanning reported in vitro IC<sub>50</sub> OATP1B1 OATP1B3 (≤1.7 <i>μ</i>M). As expected, area under plasma concentration-time curve (AUC) an OATP probe drug (i.v....
Late-stage oxidation using liver microsomes was applied to phosphodiesterase 2 inhibitor 1 reduce its clearance by cytochrome P450 enzymes, introduce renal clearance, and minimize the risk for victim drug-drug interactions. This approach yielded PF-06815189 (2) with improved physicochemical properties a mixed metabolic profile. example highlights importance of C-H diversification methods drug discovery.
Colon microbiota-based drug metabolism has received little attention thus far in the process of development, whereas role gut microbiota clinical safety and efficacy drugs become more clear. Many these studies have been performed using animal studies, but translational value data with respect to pharmacokinetics, efficacy, is largely unknown. To investigate human colon microbiota-mediated metabolism, we applied a recently developed ex vivo fermentation screening platform, which colonic...
The current study examined the bioactivation potential of a nonpeptidyl thrombopoietin receptor agonist, 1-(3-chloro-5-((4-(4-fluoro-3-(trifluoromethyl)phenyl)thiazol-2-yl)carbamoyl)pyridine-2-yl)piperidine-4-carboxylic acid (1), containing 2-carboxamido-4-arylthiazole moiety in core structure. Toxicological risks arising from P450-catalyzed C4-C5 thiazole ring opening 1 via epoxidation-->diol sequence were alleviated, since mass spectrometric analysis human liver microsome and/or hepatocyte...
N-Methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide (axitinib) is an oral inhibitor of vascular endothelial growth factor receptors 1-3, which approved for the treatment advanced renal cell cancer. Human [(14)C]-labeled clinical studies indicate axitinib's primary route clearance metabolism. The aims in vitro experiments presented herein were to identify and characterize enzymes involved axitinib metabolic clearance. In biotransformation identified a number...
In this report, we describe a method whereby lead molecules can be converted into several new analogues each using liver microsomes. Less than one micromole of substrate is incubated with microsomes (mouse, rat, hamster, guinea pig, rabbit, dog, monkey, or human) to produce multiple products which are isolated and analyzed by quantitative cryomicroprobe NMR (qNMR) spectroscopy. The solutions from qNMR analysis were then used as stocks that diluted biochemical assays. Nine human...
Replacement of hydrogen with fluorine is a useful drug design strategy when decreases in cytochrome P450 (P450) metabolic lability are needed. In this paper, facile two-step method inserting into metabolically labile sites molecules described that utilizes less than 1 mg starting material and quantitative NMR spectroscopy to ascertain the structures concentrations products. first step, hydroxyl metabolites biosynthesized using human enzymes, second step these subjected deoxyfluorination...
An experimental approach is described for late-stage lead diversification of frontrunner drug candidates using nanomole-scale amounts compounds structure-activity relationship development. The process utilizes C-H bond activation methods to explore chemical space by transforming into newly functionalized leads. A key success the utilization microcryoprobe nuclear magnetic resonance (NMR) spectroscopy, which permits use low (1-5 μmol). delivers multiple analogues from a single at as DMSO-d6...