784 results match your criteria vitro dmpk


Drug Metab Dispos 2021 Jul 30. Epub 2021 Jul 30.

DMPK, AbbVie, United States

The successful prospective incorporation of in vitro transporter kinetics in physiologically based pharmacokinetic (PBPK) models to describe drug disposition remains challenging. While determination of scaling factors to extrapolate in vitro to in vivo transporter kinetics has been facilitated by quantitative proteomics, no robust assessment comparing membrane recoveries between different cells/tissues has been made. HEK293 cells overexpressing OCT2, MATE1 and MATE2K or human kidney cortex were homogenized and centrifuged to obtain the total membrane fractions, which were subsequently subjected to liquid-liquid extraction followed by centrifugation and precipitation to isolate plasma membrane fractions. Read More

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In vitro assessment of the potential for dolutegravir to affect hepatic clearance of levonorgestrel.

HIV Med 2021 Jul 30. Epub 2021 Jul 30.

College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.

Objectives: The World Health Organization recommends that all countries adopt dolutegravir-based antiretroviral therapy as the preferred regimen for all individuals living with HIV. Levonorgestrel is a commonly used hormonal contraceptive, which undergoes drug-drug interactions with some antiretrovirals, but the potential interaction between dolutegravir and levonorgestrel has not been examined. We aimed to evaluate cytochrome P450 (CYP)-mediated levonorgestrel metabolism and quantify the effects of dolutegravir on levonorgestrel apparent intrinsic clearance (CL ) and CYP gene expression. Read More

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Preclinical and Early Clinical Development of PTC596, a Novel Small Molecule Tubulin-Binding Agent.

Mol Cancer Ther 2021 Jul 26. Epub 2021 Jul 26.

PTC Therapeutics (United States)

PTC596 is an investigational small molecule tubulin-binding agent. Unlike other tubulin-binding agents, PTC596 is orally bioavailable and is not a P-glycoprotein substrate. So as to characterize PTC596 to position the molecule for optimal clinical development, the interactions of PTC596 with tubulin using crystallography, its spectrum of preclinical in vitro anticancer activity, and its pharmacokinetic-pharmacodynamic relationship were investigated for efficacy in multiple preclinical mouse models of leiomyosarcomas and glioblastoma. Read More

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Case Study 3: Criticality of High-Quality Curve Fitting-"Getting a K" Isn't as Simple as It May Seem.

Methods Mol Biol 2021 ;2342:653-664

DMPK & Translational Modeling, AbbVie, Inc., North Chicago, IL, USA.

In this chapter, we illustrate the criticality of proper fitting of enzyme kinetic data. Simple techniques are provided to arrive at meaningful kinetic parameters, illustrated using an example, nonmonotonic data set. In the initial analysis of this data set, derived K and V parameters incorporated into PBPK models resulted in outcomes that did not adequately describe clinical data. Read More

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January 2021

Enantiospecific antitrypanosomal in vitro activity of eflornithine.

PLoS Negl Trop Dis 2021 Jul 12;15(7):e0009583. Epub 2021 Jul 12.

Unit for Pharmacokinetics and Drug Metabolism, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

The polyamine synthesis inhibitor eflornithine is a recommended treatment for the neglected tropical disease Gambian human African trypanosomiasis in late stage. This parasitic disease, transmitted by the tsetse fly, is lethal unless treated. Eflornithine is administered by repeated intravenous infusions as a racemic mixture of L-eflornithine and D-eflornithine. Read More

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Can remdesivir and its parent nucleoside GS-441524 be potential oral drugs? An and DMPK assessment.

Acta Pharm Sin B 2021 Jun 22;11(6):1607-1616. Epub 2021 Mar 22.

Center for Drug Design, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.

Remdesivir (RDV) is the only US Food and Drug Administration (FDA)-approved drug for treating COVID-19. However, RDV can only be given by intravenous route, and there is a pressing medical need for oral antivirals. Significant evidence suggests that the role of the parent nucleoside GS-441524 in the clinical outcomes of RDV could be largely underestimated. Read More

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Contribution of extra-hepatic aldehyde oxidase activity to human clearance.

Drug Metab Dispos 2021 Jun 23. Epub 2021 Jun 23.

DMPK, Takeda, United States

Aldehyde oxidase (AOX) is a soluble, cytosolic enzyme that metabolizes various N-heterocyclic compounds and organic aldehydes. It has wide tissue distribution with highest levels found in liver, kidney, and lung. Human clearance projections of AOX substrates by in vitro assessments in isolated liver fractions (cytosol, S9) and even hepatocytes have been largely under-predictive of clinical outcomes. Read More

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The Nonclinical Disposition and PK/PD Properties of GalNAc-conjugated siRNA Are Highly Predictable and Build Confidence in Translation to Man.

Drug Metab Dispos 2021 Jun 21. Epub 2021 Jun 21.

Alnylam Pharmaceuticals Inc., United States.

Conjugation of oligonucleotide therapeutics, including small interfering ribonucleic acids (siRNAs) or antisense oligonucleotides (ASOs) to N-acetylgalactosamine (GalNAc) ligands has become the primary strategy for hepatocyte-targeted delivery, and with the recent approvals of GIVLAARI® (givosiran) for the treatment of acute hepatic porphyria, OXLUMO (lumasiran) for the treatment of primary hyperoxaluria, and Leqvio® (inclisiran) for the treatment of hypercholesterolemia, the technology has been well-validated clinically. While much knowledge has been gained over decades of development there is a paucity of published literature on the DMPK properties of GalNAc-siRNA. With this in mind the goals of this mini-review are to provide an aggregate analysis of these nonclinical ADME data to build confidence on the translation of these properties to human. Read More

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Global Analysis of Models for Predicting Human Absorption: QSAR, , and Preclinical Models.

J Med Chem 2021 Jul 21;64(13):9389-9403. Epub 2021 Jun 21.

Research and Development, AbbVie Inc., 1 North Waukegan Road, North Chicago, Illinois 60064, United States.

Models intended to predict intestinal absorption are an essential part of the drug development process. Although many models exist for capturing intestinal absorption, many questions still exist around the applicability of these models to drug types like "beyond rule of 5" (bRo5) and low absorption compounds. This presents a challenge as current models have not been rigorously tested to understand intestinal absorption. Read More

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Use of Physiologically Based Pharmacokinetic Modeling for Predicting Drug-Food Interactions: Recommendations for Improving Predictive Performance of Low Confidence Food Effect Models.

AAPS J 2021 Jun 17;23(4):85. Epub 2021 Jun 17.

DMPK and Translational Modeling, AbbVie Inc., North Chicago, Illinois, USA.

Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. Read More

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Drug Metab Dispos 2021 Jun 16. Epub 2021 Jun 16.

Bioscience, AstraZeneca, United Kingdom.

Inconsistencies in pharmacokinetic parameters between individual animals in preclinical studies are a common occurrence. Often such differences between animals are simply accepted as experimental variability, rather than indications of specific differences in animal phenotype which could lead to a different interpretation of the data. The fraction unbound in plasma is one factor influencing pharmacokinetic parameters and is typically determined using pooled plasma from multiple animals making the assumption that there is limited population variance. Read More

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Feature importance of machine learning prediction models shows structurally active part and important physicochemical features in drug design.

Drug Metab Pharmacokinet 2021 Aug 3;39:100401. Epub 2021 May 3.

Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan. Electronic address:

The objective of this study was to obtain the indicators of physicochemical parameters and structurally active sites to design new chemical entities with desirable pharmacokinetic profiles by investigating the process by which machine learning prediction models arrive at their decisions, which are called explainable artificial intelligence. First, we developed the prediction models for metabolic stability, CYP inhibition, and P-gp and BCRP substrate recognition using 265 physicochemical parameters for designing the molecular structures. Four important parameters, including the well-known indicator h_logD, are common in some in vitro studies; as such, these can be used to optimize compounds simultaneously to address multiple pharmacokinetic concerns. Read More

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Translational CNS Steady-State Drug Disposition Model in Rats, Monkeys, and Humans for Quantitative Prediction of Brain-to-Plasma and Cerebrospinal Fluid-to-Plasma Unbound Concentration Ratios.

AAPS J 2021 Jun 3;23(4):81. Epub 2021 Jun 3.

Global DMPK, Preclinical and Translational Sciences, Research, Takeda Pharmaceutical Company Limited, Shonan Health Innovation Park (iPark), 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa, 251-8555, Japan.

Capturing unbound drug exposure in the brain is crucial to evaluate pharmacological effects for drugs acting on the central nervous system. However, to date, there are no reports of validated prediction models to determine the brain-to-plasma unbound concentration ratio (K) as well as the cerebrospinal fluid (CSF)-to-plasma unbound concentration ratio (K) between humans and other species. Here, we developed a translational CNS steady-state drug disposition model to predict K and K across rats, monkeys, and humans by estimating the relative activity factors (RAF) for MDR1 and BCRP in addition to scaling factors (γ and σ) using the molecular weight, logD, CSF bulk flow, and in vitro transport activities of these transporters. Read More

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Prediction of human pharmacokinetics for low-clearance compounds using pharmacokinetic data from chimeric mice with humanized livers.

Clin Transl Sci 2021 Jun 3. Epub 2021 Jun 3.

Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Development of low-clearance (CL) compounds that can be slowly metabolized is a major goal in the pharmaceutical industry. However, the pursuit of low intrinsic CL (CL ) often leads to significant challenges in evaluating the pharmacokinetics of such compounds. Although in vitro-in vivo extrapolation is widely used to predict human CL, its application has been limited for low-CL compounds because of the low turnover of parent compounds in metabolic stability assays. Read More

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Assessment of the Drug-Drug Interaction Potential of Verinurad and its Metabolites as Substrates and Inhibitors of Metabolizing Enzymes and Drug Transporters.

J Pharmacol Exp Ther 2021 Jun 1. Epub 2021 Jun 1.

DMPK, AstraZeneca R&D Gothenburg, Sweden.

Verinurad is a selective URAT1 inhibitor in development for the treatment of chronic kidney disease and heart failure. In humans, two major acyl glucuronide metabolites have been identified: direct glucuronide M1 and N-oxide glucuronide M8. Using systems recommended by regulatory agencies, we evaluated the interactions of verinurad, M1, and M8 with major drug metabolizing enzymes and transporters and the potential for clinically relevant drug-drug interactions (DDIs). Read More

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Drug Metab Dispos 2021 May 25. Epub 2021 May 25.

Merck Healthcare KGaA, Germany

Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and PXR/CAR knockout (KO) HepaRG cells, as well as a PXR reporter gene assay were used to investigate the mechanism of CYP3A4 and CYP2B6 induction by prototypical substrates and a group of compounds from the Merck Healthcare KGaA oncology drug discovery pipeline. The basal and inducible gene expression of CYP3A4 and CYP2B6 of nuclear hormone receptor (NHR) KO HepaRG relative to control HepaRG was characterized. The basal expression of CYP3A4 was higher in the PXR (9-fold) and CAR (7-fold) KO cell lines compared to control HepaRG, whereas inducibility was substantially lower. Read More

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Direct Comparison of the Prediction of the Unbound Brain-to-Plasma Partitioning Utilizing Machine Learning Approach and Mechanistic Neuropharmacokinetic Model.

AAPS J 2021 May 18;23(4):72. Epub 2021 May 18.

Global DMPK, Takeda California Inc., San Diego, California, 92121, USA.

The mechanistic neuropharmacokinetic (neuroPK) model was established to predict unbound brain-to-plasma partitioning (K) by considering in vitro efflux activities of multiple drug resistance 1 (MDR1) and breast cancer resistance protein (BCRP). Herein, we directly compare this model to a computational machine learning approach utilizing physicochemical descriptors and efflux ratios of MDR1 and BCRP-expressing cells for predicting K in rats. Two different types of machine learning techniques, Gaussian processes (GP) and random forest regression (RF), were assessed by the time and cluster-split validation methods using 640 internal compounds. Read More

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Plausible drug interaction between cyclophosphamide and voriconazole via inhibition of CYP2B6.

Drug Metab Pharmacokinet 2021 Aug 12;39:100396. Epub 2021 Apr 12.

Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8675, Japan. Electronic address:

The inhibitory activities of eight cytochrome P450 (CYP) isoenzymes for representative or suspected inhibitors of CYPs, including pesticides, were evaluated simultaneously using an in vitro cocktail incubation method to demonstrate the importance of systematic evaluation of CYP inhibitory risks in drug interaction (DI). Potent inhibition of CYP2B6 was noticeable for some azoles, including voriconazole. When voriconazole and cyclophosphamide were co-administered in mice, cyclophosphamide-induced alopecia and leukopenia were significantly suppressed by approximately 50% with increased blood concentrations of cyclophosphamide. Read More

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Ataluren metabolism: Ataluren-O-1β-acyl glucuronide is a stable circulating metabolite in mouse, rat, dog and human.

Drug Metab Pharmacokinet 2021 Jun 30;38:100393. Epub 2021 Mar 30.

PTC Therapeutics, Inc., South Plainfield, NJ, USA. Electronic address:

Ataluren is an aromatic acid derivative with a 1,2,4-oxodiazole moiety. Ataluren-O-1β-acyl glucuronide is a prominent circulatory metabolite in mice, rats, dogs, and humans following oral administration of ataluren. The objective of this paper was to evaluate the stability in vitro and in vivo of ataluren-O-1β-acyl glucuronide metabolite. Read More

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A New Guidance for the Prediction of Hepatic Clearance in the Early Drug Discovery and Development from the in Vitro-to-in Vivo Extrapolation Method and an Approach for Exploring Whether an Albumin-Mediated Hepatic Uptake Phenomenon Could be Present Under in Vivo Conditions.

J Pharm Sci 2021 Jul 20;110(7):2841-2858. Epub 2021 Apr 20.

School of Public Health, Université de Montréal, Montréal, Québec, Canada; Centre de Recherche en Santé Publique (CReSP), Montréal, Québec, Canada.

The in vitro-to-in vivo extrapolation (IVIVE) methods for predicting the hepatic clearance (CL) of drugs based on microsomal or hepatocyte data have certainly advanced; however, there is still place for improving the extrapolations from in vitro assays containing no plasma proteins. Accordingly, there is a discussion on whether the free drug hypothesis or an albumin (ALB)-mediated hepatic uptake phenomenon is the best scaling method. Therefore, the objectives of this study were to guide the prediction of CL and to diagnose which scaling method between the free drug hypothesis and ALB-mediated uptake could be more accurate; this, irrespective of the mechanism(s) governing CL if the drugs can get to the hepatocyte membrane. Read More

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Application of solid lipid nanoparticles as a long-term drug delivery platform for intramuscular and subcutaneous administration: In vitro and in vivo evaluation.

Eur J Pharm Biopharm 2021 Jun 10;163:158-170. Epub 2021 Apr 10.

University of Antwerp, Department of Pharmaceutical Technology and Biopharmacy, Universiteitsplein 1, 2610 Wilrijk, Belgium. Electronic address:

The purpose of this work was to evaluate solid lipid nanoparticles (SLNs) as a long acting injectable drug delivery platform for intramuscular and subcutaneous administration. SLNs were developed with a low (unsaturated) and high (supersaturated) drug concentration at equivalent lipid doses. The impact of the drug loading as well as the administration route for the SLNs using two model compounds with different physicochemical properties were explored for their in vitro and in vivo performance. Read More

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Investigation of the arcane inhibition of human organic anion transporter 3 by benzofuran antiarrhythmic agents.

Drug Metab Pharmacokinet 2021 Jun 20;38:100390. Epub 2021 Mar 20.

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore. Electronic address:

The combination of antiarrhythmic agents, amiodarone or dronedarone, with the anticoagulant rivaroxaban is used clinically in the management of atrial fibrillation for rhythm control and secondary stroke prevention respectively. Renal drug-drug interactions (DDIs) between amiodarone or dronedarone and rivaroxaban were previously ascribed to inhibition of rivaroxaban secretion by P-glycoprotein at the apical membrane of renal proximal tubular epithelial cells. Benzbromarone, a known inhibitor of organic anion transporter 3 (OAT3), shares a benzofuran scaffold with amiodarone and dronedarone. Read More

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The Application of Mass Spectrometry in Drug Metabolism and Pharmacokinetics.

Adv Exp Med Biol 2021 ;1310:533-550

Convergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea.

Drug metabolism and pharmacokinetics (DMPK) are fundamental in drug discovery. New chemical entities (NCEs) are typically evaluated with various in vitro and in vivo assays, which are time-consuming and labor intensive. These experiments are essential in identifying potential new drugs. Read More

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Synthesis and Characterization of the Novel Rodent-Active and CNS-Penetrant P2X7 Receptor Antagonist Lu AF27139.

J Med Chem 2021 04 6;64(8):4891-4902. Epub 2021 Apr 6.

Neuroinflammation Disease Biology Unit Lundbeck Research USA, 215 College Road, Paramus, New Jersey 07652, United States.

There remains an insufficient number of P2X7 receptor antagonists with adequate rodent potency, CNS permeability, and pharmacokinetic properties from which to evaluate CNS disease hypotheses preclinically. Herein, we describe the molecular pharmacology, safety, pharmacokinetics, and functional CNS target engagement of Lu AF27139, a novel rodent-active and CNS-penetrant P2X7 receptor antagonist. Lu AF27139 is highly selective and potent against rat, mouse, and human forms of the receptors. Read More

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Deciphering Key Interactions of Ligands with CYP3A4-Template* system.

Food Saf (Tokyo) 2021 Mar 10;9(1):10-21. Epub 2021 Feb 10.

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo194-8543, Japan.

Cytochrome P450 (CYP)-mediated metabolisms are often associated with biological and toxicological events of chemicals. A major hepatic enzyme, CYP3A4, showed clear distinctions on their catalyses even among ligands having resemble structures. To better understand mechanisms of their distinct catalyses, possible associations of ligand interactions at specific parts of CYP3A4 residues were investigated using CYP3A4-Template system developed (DMPK 2019 and 2020). Read More

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Influence of Proteome Profiles and Intracellular Drug Exposure on Differences in CYP Activity in Donor-Matched Human Liver Microsomes and Hepatocytes.

Mol Pharm 2021 04 19;18(4):1792-1805. Epub 2021 Mar 19.

Department of Pharmacy and Science for Life Laboratory, Uppsala University, 752 37 Uppsala, Sweden.

Human liver microsomes (HLM) and human hepatocytes (HH) are important systems for studies of intrinsic drug clearance (CL) in the liver. However, the CL values are often in disagreement for these two systems. Here, we investigated these differences in a side-by-side comparison of drug metabolism in HLM and HH prepared from 15 matched donors. Read More

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Population pharmacokinetic modeling and simulation to support qualification of pyridoxic acid as endogenous biomarker of OAT1/3 renal transporters.

CPT Pharmacometrics Syst Pharmacol 2021 May 1;10(5):467-477. Epub 2021 May 1.

Centre for Applied Pharmacokinetic Research, School of Health Sciences, The University of Manchester, Manchester, UK.

Renal clearance of many drugs is mediated by renal organic anion transporters OAT1/3 and inhibition of these transporters may lead to drug-drug interactions (DDIs). Pyridoxic acid (PDA) and homovanillic acid (HVA) were indicated as potential biomarkers of OAT1/3. The objective of this study was to develop a population pharmacokinetic model for PDA and HVA to support biomarker qualification. Read More

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Prediction of Oral Pharmacokinetics Using a Combination of In Silico Descriptors and In Vitro ADME Properties.

Mol Pharm 2021 03 29;18(3):1071-1079. Epub 2021 Jan 29.

Global DMPK, Takeda California Inc., San Diego, California 92121, United States.

Accurate prediction of oral pharmacokinetics remains challenging. This study investigated quantitative approaches for the prediction of the area under the plasma concentration-time curve after oral administration (AUC) to rats using the in vitro-in vivo extrapolation (IVIVE), in silico model using machine learning approaches and the combination of the in silico model and in vitro data. A set of 595 structurally diverse compounds with determined AUC at 1 mg/kg, in vitro intrinsic clearance (CL), an unbound fraction in plasma () in rats, and kinetic solubility at pH 6. Read More

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Thiophene-Pyrazolourea Derivatives as Potent, Orally Bioavailable, and Isoform-Selective JNK3 Inhibitors.

ACS Med Chem Lett 2021 Jan 13;12(1):24-29. Epub 2020 Dec 13.

Department of Biological Chemistry & Pharmacology, Ohio State University College of Medicine, Columbus, Ohio 43210, United States.

Potent JNK3 isoform selective inhibitors were developed from a thiophenyl-pyrazolourea scaffold. Through structure activity relationship (SAR) studies utilizing enzymatic and cell-based assays, and in vitro and in vivo drug metabolism and pharmacokinetic (DMPK) studies, potent and highly selective JNK3 inhibitors with oral bioavailability and brain penetrant capability were developed. Inhibitor was a potent and isoform selective JNK3 inhibitor (IC = 35 nM), had significant inhibition to only JNK3 in a panel profiling of 374 wild-type kinases, had high potency in functional cell-based assays, had high stability in human liver microsome ( = 66 min) and a clean CYP-450 inhibition profile, and was orally bioavailable and brain penetrant. Read More

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January 2021

Retention-directed and selectivity controlled chromatographic resolution: Rapid post-hoc analysis of DMPK samples to achieve high-throughput LC-MS separation.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Feb 24;1164:122514. Epub 2020 Dec 24.

Evotec, Department of Drug Metabolism & Pharmacokinetics, Abingdon, Oxon, UK.

High quality chromatographic separation underpins robustness in LC-MS, frequently the analytical method of choice for pharmaceutical drug discovery work. The potential improvements in chromatographic selectivity afforded by serial column coupling (SCC), provide a useful means to enhance the resolution of complex samples. In this work, we present a revised high-throughput form of SCC, in which just two individual mixed phase columns were coupled together and combined with a gradient-optimised, retention-directed ultra-high pressure method to achieve rapid separations, with no further method optimisation necessary. Read More

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February 2021