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J L Sebaugh - One of the best experts on this subject based on the ideXlab platform.
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Guidelines for accurate EC50/IC50 estimation
Pharmaceutical statistics, 2011Co-Authors: J L SebaughAbstract:This article provides minimum requirements for having confidence in the accuracy of EC50/IC50 estimates. Two definitions of EC50/IC50s are considered: relative and absolute. The relative EC50/IC50 is the parameter c in the 4-parameter logistic model and is the concentration corresponding to a response midway between the estimates of the lower and upper plateaus. The absolute EC50/IC50 is the response corresponding to the 50% control (the mean of the 0% and 100% assay controls). The guidelines first describe how to decide whether to use the relative EC50/IC50 or the absolute EC50/IC50. Assays for which there is no stable 100% control must use the relative EC50/IC50. Assays having a stable 100% control but for which there may be more than 5% error in the estimate of the 50% control mean should use the relative EC50/IC50. Assays that can be demonstrated to produce an accurate and stable 100% control and less than 5% error in the estimate of the 50% control mean may gain efficiency as well as accuracy by using the absolute EC50/IC50. Next, the guidelines provide rules for deciding when the EC50/IC50 estimates are reportable. The relative EC50/IC50 should only be used if there are at least two assay concentrations beyond the lower and upper bend points. The absolute EC50/IC50 should only be used if there are at least two assay concentrations whose predicted response is less than 50% and two whose predicted response is greater than 50%. A wide range of typical assay conditions are considered in the development of the guidelines.
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Guidelines for accurate EC50/IC50 estimation
Pharmaceutical Statistics, 2011Co-Authors: J L SebaughAbstract:This article provides minimum requirements for having confidence in the accuracy of EC50/IC50 estimates. Two definitions of EC50/IC50s are considered: relative and absolute. The relative EC50/IC50 is the parameter c in the 4-parameter logistic model and is the concentration corresponding to a response midway between the estimates of the lower and upper plateaus. The absolute EC50/IC50 is the response corresponding to the 50% control (the mean of the 0% and 100% assay controls). The guidelines first describe how to decide whether to use the relative EC50/IC50 or the absolute EC50/IC50. Assays for which there is no stable 100% control must use the relative EC50/IC50. Assays having a stable 100% control but for which there may be more than 5% error in the estimate of the 50% control mean should use the relative EC50/IC50. Assays that can be demonstrated to produce an accurate and stable 100% control and less than 5% error in the estimate of the 50% control mean may gain efficiency as well as accuracy by using the absolute EC50/IC50. Next, the guidelines provide rules for deciding when the EC50/IC50 estimates are reportable. The relative EC50/IC50 should only be used if there are at least two assay concentrations beyond the lower and upper bend points. The absolute EC50/IC50 should only be used if there are at least two assay concentrations whose predicted response is less than 50% and two whose predicted response is greater than 50%. A wide range of typical assay conditions are considered in the development of the guidelines. Copyright © 2010 John Wiley & Sons, Ltd.
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guidelines for accurate ec50 IC50 estimation
Pharmaceutical Statistics, 2011Co-Authors: J L SebaughAbstract:This article provides minimum requirements for having confidence in the accuracy of EC50/IC50 estimates. Two definitions of EC50/IC50s are considered: relative and absolute. The relative EC50/IC50 is the parameter c in the 4-parameter logistic model and is the concentration corresponding to a response midway between the estimates of the lower and upper plateaus. The absolute EC50/IC50 is the response corresponding to the 50% control (the mean of the 0% and 100% assay controls). The guidelines first describe how to decide whether to use the relative EC50/IC50 or the absolute EC50/IC50. Assays for which there is no stable 100% control must use the relative EC50/IC50. Assays having a stable 100% control but for which there may be more than 5% error in the estimate of the 50% control mean should use the relative EC50/IC50. Assays that can be demonstrated to produce an accurate and stable 100% control and less than 5% error in the estimate of the 50% control mean may gain efficiency as well as accuracy by using the absolute EC50/IC50. Next, the guidelines provide rules for deciding when the EC50/IC50 estimates are reportable. The relative EC50/IC50 should only be used if there are at least two assay concentrations beyond the lower and upper bend points. The absolute EC50/IC50 should only be used if there are at least two assay concentrations whose predicted response is less than 50% and two whose predicted response is greater than 50%. A wide range of typical assay conditions are considered in the development of the guidelines. Copyright © 2010 John Wiley & Sons, Ltd.
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guidelines for accurate ec50 IC50 estimation
Pharmaceutical Statistics, 2011Co-Authors: J L SebaughAbstract:This article provides minimum requirements for having confidence in the accuracy of EC50/IC50 estimates. Two definitions of EC50/IC50s are considered: relative and absolute. The relative EC50/IC50 is the parameter c in the 4-parameter logistic model and is the concentration corresponding to a response midway between the estimates of the lower and upper plateaus. The absolute EC50/IC50 is the response corresponding to the 50% control (the mean of the 0% and 100% assay controls). The guidelines first describe how to decide whether to use the relative EC50/IC50 or the absolute EC50/IC50. Assays for which there is no stable 100% control must use the relative EC50/IC50. Assays having a stable 100% control but for which there may be more than 5% error in the estimate of the 50% control mean should use the relative EC50/IC50. Assays that can be demonstrated to produce an accurate and stable 100% control and less than 5% error in the estimate of the 50% control mean may gain efficiency as well as accuracy by using the absolute EC50/IC50. Next, the guidelines provide rules for deciding when the EC50/IC50 estimates are reportable. The relative EC50/IC50 should only be used if there are at least two assay concentrations beyond the lower and upper bend points. The absolute EC50/IC50 should only be used if there are at least two assay concentrations whose predicted response is less than 50% and two whose predicted response is greater than 50%. A wide range of typical assay conditions are considered in the development of the guidelines.
Paula M C Antunes - One of the best experts on this subject based on the ideXlab platform.
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lead toxicity to lemna minor predicted using a metal speciation chemistry approach
Environmental Toxicology and Chemistry, 2014Co-Authors: Paula M C Antunes, Nancy J KreagerAbstract:In the present study, predictive measures for Pb toxicity and Lemna minor were developed from bioassays with 7 surface waters having varied chemistries (0.5–12.5 mg/L dissolved organic carbon, pH of 5.4–8.3, and water hardness of 8–266 mg/L CaCO3). As expected based on water quality, 10%, 20%, and 50% inhibitory concentration (IC10, IC20, and IC50, respectively) values expressed as percent net root elongation (%NRE) varied widely (e.g., IC20s ranging from 306 nM to >6920 nM total dissolved Pb), with unbounded values limited by Pb solubility. In considering chemical speciation, %NRE variability was better explained when both Pb hydroxides and the free lead ion were defined as bioavailable (i.e., f{OH}) and colloidal Fe(III)(OH)3 precipitates were permitted to form and sorb metals (using FeOx as the binding phase). Although cause and effect could not be established because of covariance with alkalinity (p = 0.08), water hardness correlated strongly (r2 = 0.998, p < 0.0001) with the concentration of total Pb in true solution ([Pb]T_True solution). Using these correlations as the basis for predictions (i.e., [Pb]T_True solution vs water hardness and %NRE vs f{OH}), IC20 and IC50 values produced were within a factor of 2.9 times and 2.2 times those measured, respectively. The results provide much needed effect data for L. minor and highlight the importance of chemical speciation in Pb-based risk assessments for aquatic macrophytes. Environ Toxicol Chem 2014;33:2225–2233. © 2014 SETAC
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Lead toxicity to Lemna minor predicted using a metal speciation chemistry approach
Environmental Toxicology and Chemistry, 2014Co-Authors: Paula M C Antunes, Nancy J KreagerAbstract:In the present study, predictive measures for Pb toxicity and Lemna minor were developed from bioassays with 7 surface waters having varied chemistries (0.5–12.5 mg/L dissolved organic carbon, pH of 5.4–8.3, and water hardness of 8–266 mg/L CaCO3). As expected based on water quality, 10%, 20%, and 50% inhibitory concentration (IC10, IC20, and IC50, respectively) values expressed as percent net root elongation (%NRE) varied widely (e.g., IC20s ranging from 306 nM to >6920 nM total dissolved Pb), with unbounded values limited by Pb solubility. In considering chemical speciation, %NRE variability was better explained when both Pb hydroxides and the free lead ion were defined as bioavailable (i.e., f{OH}) and colloidal Fe(III)(OH)3 precipitates were permitted to form and sorb metals (using FeOx as the binding phase). Although cause and effect could not be established because of covariance with alkalinity (p = 0.08), water hardness correlated strongly (r2 = 0.998, p
Nancy J Kreager - One of the best experts on this subject based on the ideXlab platform.
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lead toxicity to lemna minor predicted using a metal speciation chemistry approach
Environmental Toxicology and Chemistry, 2014Co-Authors: Paula M C Antunes, Nancy J KreagerAbstract:In the present study, predictive measures for Pb toxicity and Lemna minor were developed from bioassays with 7 surface waters having varied chemistries (0.5–12.5 mg/L dissolved organic carbon, pH of 5.4–8.3, and water hardness of 8–266 mg/L CaCO3). As expected based on water quality, 10%, 20%, and 50% inhibitory concentration (IC10, IC20, and IC50, respectively) values expressed as percent net root elongation (%NRE) varied widely (e.g., IC20s ranging from 306 nM to >6920 nM total dissolved Pb), with unbounded values limited by Pb solubility. In considering chemical speciation, %NRE variability was better explained when both Pb hydroxides and the free lead ion were defined as bioavailable (i.e., f{OH}) and colloidal Fe(III)(OH)3 precipitates were permitted to form and sorb metals (using FeOx as the binding phase). Although cause and effect could not be established because of covariance with alkalinity (p = 0.08), water hardness correlated strongly (r2 = 0.998, p < 0.0001) with the concentration of total Pb in true solution ([Pb]T_True solution). Using these correlations as the basis for predictions (i.e., [Pb]T_True solution vs water hardness and %NRE vs f{OH}), IC20 and IC50 values produced were within a factor of 2.9 times and 2.2 times those measured, respectively. The results provide much needed effect data for L. minor and highlight the importance of chemical speciation in Pb-based risk assessments for aquatic macrophytes. Environ Toxicol Chem 2014;33:2225–2233. © 2014 SETAC
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Lead toxicity to Lemna minor predicted using a metal speciation chemistry approach
Environmental Toxicology and Chemistry, 2014Co-Authors: Paula M C Antunes, Nancy J KreagerAbstract:In the present study, predictive measures for Pb toxicity and Lemna minor were developed from bioassays with 7 surface waters having varied chemistries (0.5–12.5 mg/L dissolved organic carbon, pH of 5.4–8.3, and water hardness of 8–266 mg/L CaCO3). As expected based on water quality, 10%, 20%, and 50% inhibitory concentration (IC10, IC20, and IC50, respectively) values expressed as percent net root elongation (%NRE) varied widely (e.g., IC20s ranging from 306 nM to >6920 nM total dissolved Pb), with unbounded values limited by Pb solubility. In considering chemical speciation, %NRE variability was better explained when both Pb hydroxides and the free lead ion were defined as bioavailable (i.e., f{OH}) and colloidal Fe(III)(OH)3 precipitates were permitted to form and sorb metals (using FeOx as the binding phase). Although cause and effect could not be established because of covariance with alkalinity (p = 0.08), water hardness correlated strongly (r2 = 0.998, p
Changhyun Oh - One of the best experts on this subject based on the ideXlab platform.
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discovery of a potent p38α mapk14 kinase inhibitor synthesis in vitro in vivo biological evaluation and docking studies
European Journal of Medicinal Chemistry, 2019Co-Authors: Mohammed I Elgamal, Hanan S Anbar, Changhyun Oh, Hamadeh TaraziAbstract:Abstract This article reports the synthesis of new triarylpyrazole derivatives possessing urea or amide linker, and their biological activities at molecular, cellular, and in vivo levels. Compound 2b was the most potent inhibitor of p38α/MAPK14 kinase (IC50 = 22 nM) among this series. Molecular docking studies were conducted to understand the kinase inhibitory variations and the basis of selectivity. Compound 2b was able to inhibit p38α/MAPK14 kinase inside HEK293 cells in nanoBRET cellular kinase assay with EC50 value of 0.55 μM, comparable to the potency of dasatinib. Compound 2b inhibited TNF-α production in lipopolysaccharide-induced THP-1 cells with IC50 value of 58 nM. In addition, compound 2b showed low potency against hERG. It is 622.38 times less potent than E−4031 against hERG, so the risk of cardiotoxicity of the compound is very minimal. Compound 2b showed also high plasma stability in vitro in human and rat plasmas. The in vivo PK profile of compound 2b is acceptable, and its antiinflammatory effect was comparable to diclofenac with no ulcerogenic side effect on stomach.
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Discovery of a potent p38α/MAPK14 kinase inhibitor: Synthesis, in vitro/in vivo biological evaluation, and docking studies
European Journal of Medicinal Chemistry, 2019Co-Authors: Mohammed I. El-gamal, Hanan S Anbar, Hamadeh Tarazi, Changhyun OhAbstract:Abstract This article reports the synthesis of new triarylpyrazole derivatives possessing urea or amide linker, and their biological activities at molecular, cellular, and in vivo levels. Compound 2b was the most potent inhibitor of p38α/MAPK14 kinase (IC50 = 22 nM) among this series. Molecular docking studies were conducted to understand the kinase inhibitory variations and the basis of selectivity. Compound 2b was able to inhibit p38α/MAPK14 kinase inside HEK293 cells in nanoBRET cellular kinase assay with EC50 value of 0.55 μM, comparable to the potency of dasatinib. Compound 2b inhibited TNF-α production in lipopolysaccharide-induced THP-1 cells with IC50 value of 58 nM. In addition, compound 2b showed low potency against hERG. It is 622.38 times less potent than E−4031 against hERG, so the risk of cardiotoxicity of the compound is very minimal. Compound 2b showed also high plasma stability in vitro in human and rat plasmas. The in vivo PK profile of compound 2b is acceptable, and its antiinflammatory effect was comparable to diclofenac with no ulcerogenic side effect on stomach.
Povl Krogsgaard-larsen - One of the best experts on this subject based on the ideXlab platform.
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Resolution, configurational assignment, and enantiopharmacology at glutamate receptors of 2‐amino‐3‐(3‐carboxy‐5‐methyl‐4‐isoxazolyl)propionic acid (ACPA) and demethyl‐ACPA
Chirality, 2001Co-Authors: Tommy N Johansen, Tine B. Stensbøl, Frank A. Sløk, Hans Brünum, Uner‐osborne, Ulf Madsen, Stine B. Vogensen, Birgitte Nielsen, Karla Frydenvang, Povl Krogsgaard-larsenAbstract:We have previously described (RS)-2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) as a potent agonist at the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor subtype of (S)-glutamic acid (Glu) receptors. We now report the chromatographic resolution of ACPA and (RS)-2-amino-3-(3-carboxy-4-isoxazolyl)propionic acid (demethyl-ACPA) using a Sumichiral OA-5000 column. The configuration of the enantiomers of both compounds have been assigned based on X-ray crystallographic analyses, supported by circular dichroism spectra and elution orders on chiral HPLC columns. Furthermore, the enantiopharmacology of ACPA and demethyl-ACPA was investigated using radioligand binding and cortical wedge electrophysiological assay systems and cloned metabotropic Glu receptors. (S)-ACPA showed high affinity in AMPA binding (IC50 = 0.025 μM), low affinity in kainic acid binding (IC50 = 3.6 μM), and potent AMPA receptor agonist activity on cortical neurons (EC50 = 0.25 μM), whereas (R)-ACPA was essentially inactive. Like (S)-ACPA, (S)-demethyl-ACPA displayed high AMPA receptor affinity (IC50 = 0.039 μM), but was found to be a relatively weak AMPA receptor agonist (EC50 = 12 μM). The stereoselectivity observed for demethyl-ACPA was high when based on AMPA receptor affinity (eudismic ratio = 250), but low when based on electrophysiological activity (eudismic ratio = 10). (R)-Demethyl-ACPA also possessed a weak NMDA receptor antagonist activity (IC50 = 220 μM). Among the enantiomers tested, only (S)-demethyl-ACPA showed activity at metabotropic receptors, being a weak antagonist at the mGlu2 receptor subtype (KB = 148 μM). Chirality 13:523–532, 2001. © 2001 Wiley-Liss, Inc.
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Structural Determinants of AMPA Agonist Activity in Analogues of 2-Amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic Acid: Synthesis and Pharmacology
Journal of Medicinal Chemistry, 2000Co-Authors: Benny Bang-andersen, Tine B. Stensbøl, Sibylle Moltzen Lenz, Haleh Ahmadian, Klaus Peter Bogeso, Ulf Madsen, Povl Krogsgaard-larsenAbstract:We have previously shown that the 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor agonist, 2-amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA, 2), binds to AMPA receptors in a manner different from that of AMPA (1) itself and that 2, in contrast to 1, also binds to kainic acid receptor sites. To elucidate the structural requirements for selective activation of the site/conformation of AMPA receptors recognized by 2, a number of isosteric analogues of 2 have now been synthesized and pharmacologically characterized. The compound 2-amino-3-(5-carboxy-3-methoxy-4-isoxazolyl)propionic acid (3a) (IC50 = 0.11 μM; EC50 = 1.2 μM), which is a regioisostere of 2 with a methoxy group substituted for the methyl group, was approximately equipotent with 2 (IC50 = 0.020 μM; EC50 = 1.0 μM) as an inhibitor of [3H]AMPA binding and as an AMPA agonist, respectively, whereas the corresponding 3-ethoxy analogue 3b (IC50 = 1.0 μM; EC50 = 4.8 μM) was slightly weaker. The analogues 3c−e, cont...
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AMPA receptor agonists: resolution, configurational assignment, and pharmacology of (+)-(S)- and (-)-(R)-2-amino-3-[3-hydroxy-5-(2-pyridyl)-isoxazol-4-yl]-propionic acid (2-Py-AMPA).
Chirality, 1997Co-Authors: Tommy N Johansen, Bjarke Ebert, Erik Falch, Povl Krogsgaard-larsenAbstract:We have previously shown that whereas (RS)-2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA) shows the characteristics of a partial agonist at (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors, (S)-APPA is a full AMPA receptor agonist and (R)-APPA a weak competitive AMPA receptor antagonist. This observation led us to introduce the new pharmacological concept, functional partial agonism. Recently we have shown that the 2-pyridyl analogue of APPA, (RS)-2-amino-3-[3-hydroxy-5-(2-pyridyl)isoxazol-4-yl]propionic acid (2-Py-AMPA), is a potent and apparently full AMPA receptor agonist, and this compound has now been resolved into (+)- and (-)-2-Py-AMPA (ee > or = 99.0%) by chiral HPLC using a Chirobiotic T column. The absolute stereochemistry of the enantiomers of APPA has previously been established by X-ray analysis, and on the basis of comparative studies of the circular dichroism spectra of the enantiomers of APPA and 2-Py-AMPA, (+)- and (-)-2-Py-AMPA were assigned the (S)- and (R)-configuration, respectively. In a series of receptor binding studies, neither enantiomer of 2-Py-AMPA showed detectable affinity for kainic acid receptor sites or different sites at the N-methyl-D-aspartic acid (NMDA) receptor complex. (+)-(S)-2-Py-AMPA was an effective inhibitor of [3H]AMPA binding (IC50 = 0.19 +/- 0.06 microM) and a potent AMPA receptor agonist in the rat cortical wedge preparation (EC50 = 4.5 +/- 0.3 microM) comparable with AMPA (IC50 = 0.040 +/- 0.01 microM; EC50 = 3.5 +/- 0.2 microM), but much more potent than (+)-(S)-APPA (IC50 = 5.5 +/- 2.2 microM; EC50 = 230 +/- 12 microM). Like (-)-(R)-APPA (IC50 > 100 microM), (-)-(R)-2-Py-AMPA (IC50 > 100 microM) did not significantly affect [3H]AMPA binding, and both compounds were weak AMPA receptor antagonists (Ki = 270 +/- 50 and 290 +/- 20 microM, respectively).
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AMPA Receptor Agonists: Synthesis, Protolytic Properties, and Pharmacology of 3-Isothiazolol Bioisosteres of Glutamic Acid
Journal of Medicinal Chemistry, 1997Co-Authors: Lisa Matzen, Anne Engesgaard, Povl Krogsgaard-larsen, Bjarke Ebert, Bente Frølund, Michael Didriksen, Jerzy W. JaroszewskiAbstract:A number of 3-isothiazolol bioisosteres of glutamic acid (1) and analogs of the AMPA receptor agonist, (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA, 2a), including (RS)-2-amino-3-(3-hydroxy-5-methylisothiazol-4-yl)propionic acid (thio-AMPA, 2b), were synthesized. Comparative in vitro pharmacological studies on this series of 3-isothiazolol and the corresponding 3-isoxazolol amino acids were performed using a series of receptor binding assays (IC50 values) and the electrophysiological rat cortical slice model (EC50 values). Whereas 2a (IC50 = 0.04 ± 0.005 μM, EC50 = 3.5 ± 0.2 μM) is markedly more potent than the tert-butyl analog ATPA (3a) (IC50 = 2.1 ± 0.16 μM, EC50 = 34 ± 2.4 μM) in [3H]AMPA binding and electrophysiological studies, 2b (IC50 = 1.8 ± 0.13 μM, EC50 = 15.0 ± 2.4 μM) was approximately equipotent with thio-ATPA (3b) (IC50 = 0.63 ± 0.07 μM, EC50 = 14 ± 1.3 μM). (RS)-2-Amino-3-(3-hydroxyisoxazol-5-yl)propionic acid (HIBO, 4a) was approximately equipotent with its thio an...