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William S Powell - One of the best experts on this subject based on the ideXlab platform.
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Structural Requirements for Activation of the 5-Oxo-6E,8Z, 11Z,14Z-Eicosatetraenoic Acid (5-Oxo-ETE) Receptor: Identification of a Mead Acid Metabolite with Potent Agonist Activity
2020Co-Authors: Pranav Patel, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Jaganmohan R Anumolu, Alain Lesimple, Orval Mamer, William S PowellAbstract:ABSTRACT The 5-lipoxygenase product 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-oxo-ETE) is a potent chemoattractant for neutrophils and eosinophils, and its actions are mediated by the oxoeicosanoid (OXE) receptor, a member of the G proteincoupled receptor family. To define the requirements for activation of the OXE receptor, we have synthesized a series of 5-oxo-6E,8Z-dienoic Acids with chain lengths between 12 and 20 carbons, as well as a series of 20-carbon 5-oxo fatty Acids, either fully saturated or containing between one and five double bonds. The effects of these compounds on neutrophils (calcium mobilization, CD11b expression, and cell migration) and eosinophils (actin polymerization) were compared with those of 5-oxo-ETE. The C 12 and C 14 analogs were without appreciable activity, whereas the C 16 5-oxo-dienoic Acid was a weak partial agonist. In contrast, the corresponding C 18 analog (5-oxo-18:2) was nearly as potent as 5-oxo-ETE. Among the C 20 analogs, the fully saturated compound had virtually no activity, whereas 5-oxo-6E-eicosenoic Acid had only weak agonist activity. In contrast, 5-oxo-6E,8Z,11Z-eicosatrienoic Acid (5-oxo-20:3) and its 8-trans isomer were approximately equipotent with 5-oxo-ETE in activating granulocytes. Because of the potent effects of 5-oxo-20:3, we investigated its formation from Mead Acid (5Z,8Z,11Z-eicosatrienoic Acid), which accumulates in dietary essential fatty Acid deficiency, by neutrophils. The main Mead Acid metabolite identified was 5-hydroxy-6,8,11-eicosatrienoic Acid, followed by 5-oxo-20:3 and two 6-trans isomers of leukotriene B 3 . We conclude that optimal activation of the OXE receptor is achieved with 5-oxo-ETE, 5-oxo-18:2, and 5-oxo-20:3, and that the latter compound could potentially be formed under conditions of essential fatty Acid deficiency. Metabolism of arachidonic Acid by the 5-lipoxygenase (5-LO) pathway leads to the formation of leukotriene (LT) B 4 , LTC 4 , LTD 4 , and 5-HET
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Novel Highly Potent and Metabolically Resistant Oxoeicosanoid (OXE) Receptor Antagonists That Block the Actions of the Granulocyte Chemoattractant 5‑Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE)
2018Co-Authors: Shishir Chourey, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Chintam Nagendra Reddy, Irina Slobodchikova, Dajana Vuckovic, Rui Wang, William S PowellAbstract:5-Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is a potent lipid mediator that induces tissue eosinophilia via the selective OXE receptor (OXE-R), which is an attractive therapeutic target in eosinophilic diseases. We previously identified indole OXE-R antagonists that block 5-oxo-ETE-induced primate eosinophil activation. Although these compounds possess good oral absorption, their plasma levels decline rapidly due to extensive oxidation of their hexyl side chain. We have now succeeded in dramatically increasing antagonist potency and resistance to metabolism by replacing the hexyl group with phenylpentyl or phenylhexyl side chains. Compared with our previous lead compound S-230, our most potent antagonist, S-C025, has an IC50 (120 pM) over 80 times lower and a substantially longer plasma half-life. A single major metabolite, which retains antagonist activity (IC50, 690 pM) and has a prolonged lifetime in plasma was observed. These new highly potent OXE-R antagonists may provide a novel strategy for the treatment of eosinophilic disorders like asthma
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Pharmacokinetics and Metabolism of Selective Oxoeicosanoid (OXE) Receptor Antagonists and Their Effects on 5‑Oxo-6,8,11,14-Eicosatetraenoic Acid (5-Oxo-ETE)-Induced Granulocyte Activation in Monkeys
2016Co-Authors: Chantal Cossette, Joshua Rokach, Sylvie Gravel, Shishir Chourey, Chintam Nagendra Reddy, Vivek Gore, Irina Slobodchikova, Dajana Vuckovic, William S PowellAbstract:The potent eosinophil chemoattractant 5-oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is a 5-lipoxygenase product that acts via the selective OXE receptor, which is present in many species, but not rodents. We previously reported that the indole 230 is a potent human OXE receptor antagonist. The objective of the present study was to determine whether the monkey would be a suitable animal model to investigate its pharmaceutical potential. We found that monkey leukocytes synthesize and respond to 5-oxo-ETE and that 230 is a potent antagonist of the OXE receptor in monkey eosinophils. Pharmacokinetic studies revealed that 230 appears rapidly in the blood following oral administration. Using chemically synthesized standards, we identified the major microsomal and plasma metabolites of 230 as products of ω2-hydroxylation of the alkyl side chain. These studies demonstrate that the monkey is a promising animal model to investigate the drug potential of OXE receptor antagonists
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oxidative stress induced changes in pyridine nucleotides and chemoattractant 5 lipoxygenase products in aging neutrophils
Free Radical Biology and Medicine, 2009Co-Authors: Francois D Graham, Joshua Rokach, Karlrudolf Erlemann, Sylvie Gravel, William S PowellAbstract:Abstract Neutrophils spontaneously undergo apoptosis, which is associated with increased oxidative stress. We found that there is a dramatic shift in the formation of 5-lipoxygenase products during this process. Freshly isolated neutrophils rapidly convert leukotriene B4 (LTB4) and 5-hydroxy-6,8,11,14-Eicosatetraenoic Acid (5-HETE) to their biologically inactive ω-oxidation products. However, ω-oxidation is impaired in neutrophils cultured for 24 h, when only 25% of the cells are nonapoptotic, resulting in the persistence of LTB4 and a dramatic shift in 5-HETE metabolism to the potent granulocyte chemoattractant 5-oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE). The reduced ω-oxidation activity seems to be due to a reduction in LTB4 20-hydroxylase activity, whereas the increased 5-oxo-ETE formation is caused by a dramatic increase in the 5-hydroxyeicosanoid dehydrogenase cofactor NADP+. NAD+, but not NADPH, also increased, as did the GSSG/GSH ratio, indicative of oxidative stress. The changes in 5-HETE metabolism and pyridine nucleotides were inhibited by antiapoptotic agents (GM-CSF, forskolin) and antioxidants (diphenylene iodonium, catalase, deferoxamine), suggesting the involvement of H2O2 and possibly other reactive oxygen species. These results suggest that in severe inflammation, aging neutrophils that have evaded rapid uptake by macrophages may produce increased amounts of the chemoattractants 5-oxo-ETE and LTB4, resulting in delayed resolution or exacerbation of the inflammatory process.
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structural requirements for activation of the 5 oxo 6e 8z 11z 14z Eicosatetraenoic Acid 5 oxo ete receptor identification of a mead Acid metabolite with potent agonist activity
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Pranav Patel, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Jaganmohan R Anumolu, Alain Lesimple, Orval Mamer, William S PowellAbstract:The 5-lipoxygenase product 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-oxo-ETE) is a potent chemoattractant for neutrophils and eosinophils, and its actions are mediated by the oxoeicosanoid (OXE) receptor, a member of the G protein-coupled receptor family. To define the requirements for activation of the OXE receptor, we have synthesized a series of 5-oxo-6E,8Z-dienoic Acids with chain lengths between 12 and 20 carbons, as well as a series of 20-carbon 5-oxo fatty Acids, either fully saturated or containing between one and five double bonds. The effects of these compounds on neutrophils (calcium mobilization, CD11b expression, and cell migration) and eosinophils (actin polymerization) were compared with those of 5-oxo-ETE. The C12 and C14 analogs were without appreciable activity, whereas the C16 5-oxo-dienoic Acid was a weak partial agonist. In contrast, the corresponding C18 analog (5-oxo-18:2) was nearly as potent as 5-oxo-ETE. Among the C20 analogs, the fully saturated compound had virtually no activity, whereas 5-oxo-6E-eicosenoic Acid had only weak agonist activity. In contrast, 5-oxo-6E,8Z,11Z-eicosatrienoic Acid (5-oxo-20:3) and its 8-trans isomer were approximately equipotent with 5-oxo-ETE in activating granulocytes. Because of the potent effects of 5-oxo-20:3, we investigated its formation from Mead Acid (5Z,8Z,11Z-eicosatrienoic Acid), which accumulates in dietary essential fatty Acid deficiency, by neutrophils. The main Mead Acid metabolite identified was 5-hydroxy-6,8,11-eicosatrienoic Acid, followed by 5-oxo-20:3 and two 6-trans isomers of leukotriene B(3). We conclude that optimal activation of the OXE receptor is achieved with 5-oxo-ETE, 5-oxo-18:2, and 5-oxo-20:3, and that the latter compound could potentially be formed under conditions of essential fatty Acid deficiency.
Joshua Rokach - One of the best experts on this subject based on the ideXlab platform.
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Structural Requirements for Activation of the 5-Oxo-6E,8Z, 11Z,14Z-Eicosatetraenoic Acid (5-Oxo-ETE) Receptor: Identification of a Mead Acid Metabolite with Potent Agonist Activity
2020Co-Authors: Pranav Patel, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Jaganmohan R Anumolu, Alain Lesimple, Orval Mamer, William S PowellAbstract:ABSTRACT The 5-lipoxygenase product 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-oxo-ETE) is a potent chemoattractant for neutrophils and eosinophils, and its actions are mediated by the oxoeicosanoid (OXE) receptor, a member of the G proteincoupled receptor family. To define the requirements for activation of the OXE receptor, we have synthesized a series of 5-oxo-6E,8Z-dienoic Acids with chain lengths between 12 and 20 carbons, as well as a series of 20-carbon 5-oxo fatty Acids, either fully saturated or containing between one and five double bonds. The effects of these compounds on neutrophils (calcium mobilization, CD11b expression, and cell migration) and eosinophils (actin polymerization) were compared with those of 5-oxo-ETE. The C 12 and C 14 analogs were without appreciable activity, whereas the C 16 5-oxo-dienoic Acid was a weak partial agonist. In contrast, the corresponding C 18 analog (5-oxo-18:2) was nearly as potent as 5-oxo-ETE. Among the C 20 analogs, the fully saturated compound had virtually no activity, whereas 5-oxo-6E-eicosenoic Acid had only weak agonist activity. In contrast, 5-oxo-6E,8Z,11Z-eicosatrienoic Acid (5-oxo-20:3) and its 8-trans isomer were approximately equipotent with 5-oxo-ETE in activating granulocytes. Because of the potent effects of 5-oxo-20:3, we investigated its formation from Mead Acid (5Z,8Z,11Z-eicosatrienoic Acid), which accumulates in dietary essential fatty Acid deficiency, by neutrophils. The main Mead Acid metabolite identified was 5-hydroxy-6,8,11-eicosatrienoic Acid, followed by 5-oxo-20:3 and two 6-trans isomers of leukotriene B 3 . We conclude that optimal activation of the OXE receptor is achieved with 5-oxo-ETE, 5-oxo-18:2, and 5-oxo-20:3, and that the latter compound could potentially be formed under conditions of essential fatty Acid deficiency. Metabolism of arachidonic Acid by the 5-lipoxygenase (5-LO) pathway leads to the formation of leukotriene (LT) B 4 , LTC 4 , LTD 4 , and 5-HET
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Novel Highly Potent and Metabolically Resistant Oxoeicosanoid (OXE) Receptor Antagonists That Block the Actions of the Granulocyte Chemoattractant 5‑Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE)
2018Co-Authors: Shishir Chourey, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Chintam Nagendra Reddy, Irina Slobodchikova, Dajana Vuckovic, Rui Wang, William S PowellAbstract:5-Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is a potent lipid mediator that induces tissue eosinophilia via the selective OXE receptor (OXE-R), which is an attractive therapeutic target in eosinophilic diseases. We previously identified indole OXE-R antagonists that block 5-oxo-ETE-induced primate eosinophil activation. Although these compounds possess good oral absorption, their plasma levels decline rapidly due to extensive oxidation of their hexyl side chain. We have now succeeded in dramatically increasing antagonist potency and resistance to metabolism by replacing the hexyl group with phenylpentyl or phenylhexyl side chains. Compared with our previous lead compound S-230, our most potent antagonist, S-C025, has an IC50 (120 pM) over 80 times lower and a substantially longer plasma half-life. A single major metabolite, which retains antagonist activity (IC50, 690 pM) and has a prolonged lifetime in plasma was observed. These new highly potent OXE-R antagonists may provide a novel strategy for the treatment of eosinophilic disorders like asthma
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Pharmacokinetics and Metabolism of Selective Oxoeicosanoid (OXE) Receptor Antagonists and Their Effects on 5‑Oxo-6,8,11,14-Eicosatetraenoic Acid (5-Oxo-ETE)-Induced Granulocyte Activation in Monkeys
2016Co-Authors: Chantal Cossette, Joshua Rokach, Sylvie Gravel, Shishir Chourey, Chintam Nagendra Reddy, Vivek Gore, Irina Slobodchikova, Dajana Vuckovic, William S PowellAbstract:The potent eosinophil chemoattractant 5-oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is a 5-lipoxygenase product that acts via the selective OXE receptor, which is present in many species, but not rodents. We previously reported that the indole 230 is a potent human OXE receptor antagonist. The objective of the present study was to determine whether the monkey would be a suitable animal model to investigate its pharmaceutical potential. We found that monkey leukocytes synthesize and respond to 5-oxo-ETE and that 230 is a potent antagonist of the OXE receptor in monkey eosinophils. Pharmacokinetic studies revealed that 230 appears rapidly in the blood following oral administration. Using chemically synthesized standards, we identified the major microsomal and plasma metabolites of 230 as products of ω2-hydroxylation of the alkyl side chain. These studies demonstrate that the monkey is a promising animal model to investigate the drug potential of OXE receptor antagonists
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Two Potent OXE‑R Antagonists: Assignment of Stereochemistry
2014Co-Authors: Pranav Patel, Sylvie Gravel, Shishir Chourey, Chintam Nagendra Reddy, Vivek Gore, Yannick P. Ouedraogo, William S. Powell, Joshua RokachAbstract:5-Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is formed by the oxidation of 5-hydroxy-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-HETE), which is a major metabolite of enzymatic oxidation of arachidonic Acid (AA). 5-Oxo-ETE is the most potent lipid chemoattractant for human eosinophils. Its actions are mediated by the selective OXE receptor, which is therefore an attractive target in eosinophilic diseases such as allergic rhinitis and asthma. Recently, we have reported two excellent OXE receptor antagonists that have IC50 values at low nanomolar concentrations. Each of these antagonists has a chiral center, and the isolation of the individual enantiomers by chiral high-performance liquid chromatography (HPLC) revealed that in each case one enantiomer is over 300 times more potent than the other. To unambiguously assign the stereochemistry of these enantiomers and to provide access to larger amounts of the active compounds for biological testing, we report here their total synthesis
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oxidative stress induced changes in pyridine nucleotides and chemoattractant 5 lipoxygenase products in aging neutrophils
Free Radical Biology and Medicine, 2009Co-Authors: Francois D Graham, Joshua Rokach, Karlrudolf Erlemann, Sylvie Gravel, William S PowellAbstract:Abstract Neutrophils spontaneously undergo apoptosis, which is associated with increased oxidative stress. We found that there is a dramatic shift in the formation of 5-lipoxygenase products during this process. Freshly isolated neutrophils rapidly convert leukotriene B4 (LTB4) and 5-hydroxy-6,8,11,14-Eicosatetraenoic Acid (5-HETE) to their biologically inactive ω-oxidation products. However, ω-oxidation is impaired in neutrophils cultured for 24 h, when only 25% of the cells are nonapoptotic, resulting in the persistence of LTB4 and a dramatic shift in 5-HETE metabolism to the potent granulocyte chemoattractant 5-oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE). The reduced ω-oxidation activity seems to be due to a reduction in LTB4 20-hydroxylase activity, whereas the increased 5-oxo-ETE formation is caused by a dramatic increase in the 5-hydroxyeicosanoid dehydrogenase cofactor NADP+. NAD+, but not NADPH, also increased, as did the GSSG/GSH ratio, indicative of oxidative stress. The changes in 5-HETE metabolism and pyridine nucleotides were inhibited by antiapoptotic agents (GM-CSF, forskolin) and antioxidants (diphenylene iodonium, catalase, deferoxamine), suggesting the involvement of H2O2 and possibly other reactive oxygen species. These results suggest that in severe inflammation, aging neutrophils that have evaded rapid uptake by macrophages may produce increased amounts of the chemoattractants 5-oxo-ETE and LTB4, resulting in delayed resolution or exacerbation of the inflammatory process.
Sylvie Gravel - One of the best experts on this subject based on the ideXlab platform.
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Structural Requirements for Activation of the 5-Oxo-6E,8Z, 11Z,14Z-Eicosatetraenoic Acid (5-Oxo-ETE) Receptor: Identification of a Mead Acid Metabolite with Potent Agonist Activity
2020Co-Authors: Pranav Patel, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Jaganmohan R Anumolu, Alain Lesimple, Orval Mamer, William S PowellAbstract:ABSTRACT The 5-lipoxygenase product 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-oxo-ETE) is a potent chemoattractant for neutrophils and eosinophils, and its actions are mediated by the oxoeicosanoid (OXE) receptor, a member of the G proteincoupled receptor family. To define the requirements for activation of the OXE receptor, we have synthesized a series of 5-oxo-6E,8Z-dienoic Acids with chain lengths between 12 and 20 carbons, as well as a series of 20-carbon 5-oxo fatty Acids, either fully saturated or containing between one and five double bonds. The effects of these compounds on neutrophils (calcium mobilization, CD11b expression, and cell migration) and eosinophils (actin polymerization) were compared with those of 5-oxo-ETE. The C 12 and C 14 analogs were without appreciable activity, whereas the C 16 5-oxo-dienoic Acid was a weak partial agonist. In contrast, the corresponding C 18 analog (5-oxo-18:2) was nearly as potent as 5-oxo-ETE. Among the C 20 analogs, the fully saturated compound had virtually no activity, whereas 5-oxo-6E-eicosenoic Acid had only weak agonist activity. In contrast, 5-oxo-6E,8Z,11Z-eicosatrienoic Acid (5-oxo-20:3) and its 8-trans isomer were approximately equipotent with 5-oxo-ETE in activating granulocytes. Because of the potent effects of 5-oxo-20:3, we investigated its formation from Mead Acid (5Z,8Z,11Z-eicosatrienoic Acid), which accumulates in dietary essential fatty Acid deficiency, by neutrophils. The main Mead Acid metabolite identified was 5-hydroxy-6,8,11-eicosatrienoic Acid, followed by 5-oxo-20:3 and two 6-trans isomers of leukotriene B 3 . We conclude that optimal activation of the OXE receptor is achieved with 5-oxo-ETE, 5-oxo-18:2, and 5-oxo-20:3, and that the latter compound could potentially be formed under conditions of essential fatty Acid deficiency. Metabolism of arachidonic Acid by the 5-lipoxygenase (5-LO) pathway leads to the formation of leukotriene (LT) B 4 , LTC 4 , LTD 4 , and 5-HET
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Novel Highly Potent and Metabolically Resistant Oxoeicosanoid (OXE) Receptor Antagonists That Block the Actions of the Granulocyte Chemoattractant 5‑Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE)
2018Co-Authors: Shishir Chourey, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Chintam Nagendra Reddy, Irina Slobodchikova, Dajana Vuckovic, Rui Wang, William S PowellAbstract:5-Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is a potent lipid mediator that induces tissue eosinophilia via the selective OXE receptor (OXE-R), which is an attractive therapeutic target in eosinophilic diseases. We previously identified indole OXE-R antagonists that block 5-oxo-ETE-induced primate eosinophil activation. Although these compounds possess good oral absorption, their plasma levels decline rapidly due to extensive oxidation of their hexyl side chain. We have now succeeded in dramatically increasing antagonist potency and resistance to metabolism by replacing the hexyl group with phenylpentyl or phenylhexyl side chains. Compared with our previous lead compound S-230, our most potent antagonist, S-C025, has an IC50 (120 pM) over 80 times lower and a substantially longer plasma half-life. A single major metabolite, which retains antagonist activity (IC50, 690 pM) and has a prolonged lifetime in plasma was observed. These new highly potent OXE-R antagonists may provide a novel strategy for the treatment of eosinophilic disorders like asthma
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Pharmacokinetics and Metabolism of Selective Oxoeicosanoid (OXE) Receptor Antagonists and Their Effects on 5‑Oxo-6,8,11,14-Eicosatetraenoic Acid (5-Oxo-ETE)-Induced Granulocyte Activation in Monkeys
2016Co-Authors: Chantal Cossette, Joshua Rokach, Sylvie Gravel, Shishir Chourey, Chintam Nagendra Reddy, Vivek Gore, Irina Slobodchikova, Dajana Vuckovic, William S PowellAbstract:The potent eosinophil chemoattractant 5-oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is a 5-lipoxygenase product that acts via the selective OXE receptor, which is present in many species, but not rodents. We previously reported that the indole 230 is a potent human OXE receptor antagonist. The objective of the present study was to determine whether the monkey would be a suitable animal model to investigate its pharmaceutical potential. We found that monkey leukocytes synthesize and respond to 5-oxo-ETE and that 230 is a potent antagonist of the OXE receptor in monkey eosinophils. Pharmacokinetic studies revealed that 230 appears rapidly in the blood following oral administration. Using chemically synthesized standards, we identified the major microsomal and plasma metabolites of 230 as products of ω2-hydroxylation of the alkyl side chain. These studies demonstrate that the monkey is a promising animal model to investigate the drug potential of OXE receptor antagonists
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Two Potent OXE‑R Antagonists: Assignment of Stereochemistry
2014Co-Authors: Pranav Patel, Sylvie Gravel, Shishir Chourey, Chintam Nagendra Reddy, Vivek Gore, Yannick P. Ouedraogo, William S. Powell, Joshua RokachAbstract:5-Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is formed by the oxidation of 5-hydroxy-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-HETE), which is a major metabolite of enzymatic oxidation of arachidonic Acid (AA). 5-Oxo-ETE is the most potent lipid chemoattractant for human eosinophils. Its actions are mediated by the selective OXE receptor, which is therefore an attractive target in eosinophilic diseases such as allergic rhinitis and asthma. Recently, we have reported two excellent OXE receptor antagonists that have IC50 values at low nanomolar concentrations. Each of these antagonists has a chiral center, and the isolation of the individual enantiomers by chiral high-performance liquid chromatography (HPLC) revealed that in each case one enantiomer is over 300 times more potent than the other. To unambiguously assign the stereochemistry of these enantiomers and to provide access to larger amounts of the active compounds for biological testing, we report here their total synthesis
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oxidative stress induced changes in pyridine nucleotides and chemoattractant 5 lipoxygenase products in aging neutrophils
Free Radical Biology and Medicine, 2009Co-Authors: Francois D Graham, Joshua Rokach, Karlrudolf Erlemann, Sylvie Gravel, William S PowellAbstract:Abstract Neutrophils spontaneously undergo apoptosis, which is associated with increased oxidative stress. We found that there is a dramatic shift in the formation of 5-lipoxygenase products during this process. Freshly isolated neutrophils rapidly convert leukotriene B4 (LTB4) and 5-hydroxy-6,8,11,14-Eicosatetraenoic Acid (5-HETE) to their biologically inactive ω-oxidation products. However, ω-oxidation is impaired in neutrophils cultured for 24 h, when only 25% of the cells are nonapoptotic, resulting in the persistence of LTB4 and a dramatic shift in 5-HETE metabolism to the potent granulocyte chemoattractant 5-oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE). The reduced ω-oxidation activity seems to be due to a reduction in LTB4 20-hydroxylase activity, whereas the increased 5-oxo-ETE formation is caused by a dramatic increase in the 5-hydroxyeicosanoid dehydrogenase cofactor NADP+. NAD+, but not NADPH, also increased, as did the GSSG/GSH ratio, indicative of oxidative stress. The changes in 5-HETE metabolism and pyridine nucleotides were inhibited by antiapoptotic agents (GM-CSF, forskolin) and antioxidants (diphenylene iodonium, catalase, deferoxamine), suggesting the involvement of H2O2 and possibly other reactive oxygen species. These results suggest that in severe inflammation, aging neutrophils that have evaded rapid uptake by macrophages may produce increased amounts of the chemoattractants 5-oxo-ETE and LTB4, resulting in delayed resolution or exacerbation of the inflammatory process.
Pranav Patel - One of the best experts on this subject based on the ideXlab platform.
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Structural Requirements for Activation of the 5-Oxo-6E,8Z, 11Z,14Z-Eicosatetraenoic Acid (5-Oxo-ETE) Receptor: Identification of a Mead Acid Metabolite with Potent Agonist Activity
2020Co-Authors: Pranav Patel, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Jaganmohan R Anumolu, Alain Lesimple, Orval Mamer, William S PowellAbstract:ABSTRACT The 5-lipoxygenase product 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-oxo-ETE) is a potent chemoattractant for neutrophils and eosinophils, and its actions are mediated by the oxoeicosanoid (OXE) receptor, a member of the G proteincoupled receptor family. To define the requirements for activation of the OXE receptor, we have synthesized a series of 5-oxo-6E,8Z-dienoic Acids with chain lengths between 12 and 20 carbons, as well as a series of 20-carbon 5-oxo fatty Acids, either fully saturated or containing between one and five double bonds. The effects of these compounds on neutrophils (calcium mobilization, CD11b expression, and cell migration) and eosinophils (actin polymerization) were compared with those of 5-oxo-ETE. The C 12 and C 14 analogs were without appreciable activity, whereas the C 16 5-oxo-dienoic Acid was a weak partial agonist. In contrast, the corresponding C 18 analog (5-oxo-18:2) was nearly as potent as 5-oxo-ETE. Among the C 20 analogs, the fully saturated compound had virtually no activity, whereas 5-oxo-6E-eicosenoic Acid had only weak agonist activity. In contrast, 5-oxo-6E,8Z,11Z-eicosatrienoic Acid (5-oxo-20:3) and its 8-trans isomer were approximately equipotent with 5-oxo-ETE in activating granulocytes. Because of the potent effects of 5-oxo-20:3, we investigated its formation from Mead Acid (5Z,8Z,11Z-eicosatrienoic Acid), which accumulates in dietary essential fatty Acid deficiency, by neutrophils. The main Mead Acid metabolite identified was 5-hydroxy-6,8,11-eicosatrienoic Acid, followed by 5-oxo-20:3 and two 6-trans isomers of leukotriene B 3 . We conclude that optimal activation of the OXE receptor is achieved with 5-oxo-ETE, 5-oxo-18:2, and 5-oxo-20:3, and that the latter compound could potentially be formed under conditions of essential fatty Acid deficiency. Metabolism of arachidonic Acid by the 5-lipoxygenase (5-LO) pathway leads to the formation of leukotriene (LT) B 4 , LTC 4 , LTD 4 , and 5-HET
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Two Potent OXE‑R Antagonists: Assignment of Stereochemistry
2014Co-Authors: Pranav Patel, Sylvie Gravel, Shishir Chourey, Chintam Nagendra Reddy, Vivek Gore, Yannick P. Ouedraogo, William S. Powell, Joshua RokachAbstract:5-Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is formed by the oxidation of 5-hydroxy-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-HETE), which is a major metabolite of enzymatic oxidation of arachidonic Acid (AA). 5-Oxo-ETE is the most potent lipid chemoattractant for human eosinophils. Its actions are mediated by the selective OXE receptor, which is therefore an attractive target in eosinophilic diseases such as allergic rhinitis and asthma. Recently, we have reported two excellent OXE receptor antagonists that have IC50 values at low nanomolar concentrations. Each of these antagonists has a chiral center, and the isolation of the individual enantiomers by chiral high-performance liquid chromatography (HPLC) revealed that in each case one enantiomer is over 300 times more potent than the other. To unambiguously assign the stereochemistry of these enantiomers and to provide access to larger amounts of the active compounds for biological testing, we report here their total synthesis
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structural requirements for activation of the 5 oxo 6e 8z 11z 14z Eicosatetraenoic Acid 5 oxo ete receptor identification of a mead Acid metabolite with potent agonist activity
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Pranav Patel, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Jaganmohan R Anumolu, Alain Lesimple, Orval Mamer, William S PowellAbstract:The 5-lipoxygenase product 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-oxo-ETE) is a potent chemoattractant for neutrophils and eosinophils, and its actions are mediated by the oxoeicosanoid (OXE) receptor, a member of the G protein-coupled receptor family. To define the requirements for activation of the OXE receptor, we have synthesized a series of 5-oxo-6E,8Z-dienoic Acids with chain lengths between 12 and 20 carbons, as well as a series of 20-carbon 5-oxo fatty Acids, either fully saturated or containing between one and five double bonds. The effects of these compounds on neutrophils (calcium mobilization, CD11b expression, and cell migration) and eosinophils (actin polymerization) were compared with those of 5-oxo-ETE. The C12 and C14 analogs were without appreciable activity, whereas the C16 5-oxo-dienoic Acid was a weak partial agonist. In contrast, the corresponding C18 analog (5-oxo-18:2) was nearly as potent as 5-oxo-ETE. Among the C20 analogs, the fully saturated compound had virtually no activity, whereas 5-oxo-6E-eicosenoic Acid had only weak agonist activity. In contrast, 5-oxo-6E,8Z,11Z-eicosatrienoic Acid (5-oxo-20:3) and its 8-trans isomer were approximately equipotent with 5-oxo-ETE in activating granulocytes. Because of the potent effects of 5-oxo-20:3, we investigated its formation from Mead Acid (5Z,8Z,11Z-eicosatrienoic Acid), which accumulates in dietary essential fatty Acid deficiency, by neutrophils. The main Mead Acid metabolite identified was 5-hydroxy-6,8,11-eicosatrienoic Acid, followed by 5-oxo-20:3 and two 6-trans isomers of leukotriene B(3). We conclude that optimal activation of the OXE receptor is achieved with 5-oxo-ETE, 5-oxo-18:2, and 5-oxo-20:3, and that the latter compound could potentially be formed under conditions of essential fatty Acid deficiency.
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Structural Requirements for Activation of the 5-Oxo-6E,8Z, 11Z,14Z-Eicosatetraenoic Acid (5-Oxo-ETE) Receptor: Identification of a Mead Acid Metabolite with Potent Agonist Activity
2020Co-Authors: Pranav Patel, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Jaganmohan R Anumolu, Alain Lesimple, Orval Mamer, William S PowellAbstract:ABSTRACT The 5-lipoxygenase product 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-oxo-ETE) is a potent chemoattractant for neutrophils and eosinophils, and its actions are mediated by the oxoeicosanoid (OXE) receptor, a member of the G proteincoupled receptor family. To define the requirements for activation of the OXE receptor, we have synthesized a series of 5-oxo-6E,8Z-dienoic Acids with chain lengths between 12 and 20 carbons, as well as a series of 20-carbon 5-oxo fatty Acids, either fully saturated or containing between one and five double bonds. The effects of these compounds on neutrophils (calcium mobilization, CD11b expression, and cell migration) and eosinophils (actin polymerization) were compared with those of 5-oxo-ETE. The C 12 and C 14 analogs were without appreciable activity, whereas the C 16 5-oxo-dienoic Acid was a weak partial agonist. In contrast, the corresponding C 18 analog (5-oxo-18:2) was nearly as potent as 5-oxo-ETE. Among the C 20 analogs, the fully saturated compound had virtually no activity, whereas 5-oxo-6E-eicosenoic Acid had only weak agonist activity. In contrast, 5-oxo-6E,8Z,11Z-eicosatrienoic Acid (5-oxo-20:3) and its 8-trans isomer were approximately equipotent with 5-oxo-ETE in activating granulocytes. Because of the potent effects of 5-oxo-20:3, we investigated its formation from Mead Acid (5Z,8Z,11Z-eicosatrienoic Acid), which accumulates in dietary essential fatty Acid deficiency, by neutrophils. The main Mead Acid metabolite identified was 5-hydroxy-6,8,11-eicosatrienoic Acid, followed by 5-oxo-20:3 and two 6-trans isomers of leukotriene B 3 . We conclude that optimal activation of the OXE receptor is achieved with 5-oxo-ETE, 5-oxo-18:2, and 5-oxo-20:3, and that the latter compound could potentially be formed under conditions of essential fatty Acid deficiency. Metabolism of arachidonic Acid by the 5-lipoxygenase (5-LO) pathway leads to the formation of leukotriene (LT) B 4 , LTC 4 , LTD 4 , and 5-HET
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Novel Highly Potent and Metabolically Resistant Oxoeicosanoid (OXE) Receptor Antagonists That Block the Actions of the Granulocyte Chemoattractant 5‑Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE)
2018Co-Authors: Shishir Chourey, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Chintam Nagendra Reddy, Irina Slobodchikova, Dajana Vuckovic, Rui Wang, William S PowellAbstract:5-Oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is a potent lipid mediator that induces tissue eosinophilia via the selective OXE receptor (OXE-R), which is an attractive therapeutic target in eosinophilic diseases. We previously identified indole OXE-R antagonists that block 5-oxo-ETE-induced primate eosinophil activation. Although these compounds possess good oral absorption, their plasma levels decline rapidly due to extensive oxidation of their hexyl side chain. We have now succeeded in dramatically increasing antagonist potency and resistance to metabolism by replacing the hexyl group with phenylpentyl or phenylhexyl side chains. Compared with our previous lead compound S-230, our most potent antagonist, S-C025, has an IC50 (120 pM) over 80 times lower and a substantially longer plasma half-life. A single major metabolite, which retains antagonist activity (IC50, 690 pM) and has a prolonged lifetime in plasma was observed. These new highly potent OXE-R antagonists may provide a novel strategy for the treatment of eosinophilic disorders like asthma
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Pharmacokinetics and Metabolism of Selective Oxoeicosanoid (OXE) Receptor Antagonists and Their Effects on 5‑Oxo-6,8,11,14-Eicosatetraenoic Acid (5-Oxo-ETE)-Induced Granulocyte Activation in Monkeys
2016Co-Authors: Chantal Cossette, Joshua Rokach, Sylvie Gravel, Shishir Chourey, Chintam Nagendra Reddy, Vivek Gore, Irina Slobodchikova, Dajana Vuckovic, William S PowellAbstract:The potent eosinophil chemoattractant 5-oxo-6,8,11,14-Eicosatetraenoic Acid (5-oxo-ETE) is a 5-lipoxygenase product that acts via the selective OXE receptor, which is present in many species, but not rodents. We previously reported that the indole 230 is a potent human OXE receptor antagonist. The objective of the present study was to determine whether the monkey would be a suitable animal model to investigate its pharmaceutical potential. We found that monkey leukocytes synthesize and respond to 5-oxo-ETE and that 230 is a potent antagonist of the OXE receptor in monkey eosinophils. Pharmacokinetic studies revealed that 230 appears rapidly in the blood following oral administration. Using chemically synthesized standards, we identified the major microsomal and plasma metabolites of 230 as products of ω2-hydroxylation of the alkyl side chain. These studies demonstrate that the monkey is a promising animal model to investigate the drug potential of OXE receptor antagonists
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structural requirements for activation of the 5 oxo 6e 8z 11z 14z Eicosatetraenoic Acid 5 oxo ete receptor identification of a mead Acid metabolite with potent agonist activity
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Pranav Patel, Joshua Rokach, Sylvie Gravel, Chantal Cossette, Jaganmohan R Anumolu, Alain Lesimple, Orval Mamer, William S PowellAbstract:The 5-lipoxygenase product 5-oxo-6E,8Z,11Z,14Z-Eicosatetraenoic Acid (5-oxo-ETE) is a potent chemoattractant for neutrophils and eosinophils, and its actions are mediated by the oxoeicosanoid (OXE) receptor, a member of the G protein-coupled receptor family. To define the requirements for activation of the OXE receptor, we have synthesized a series of 5-oxo-6E,8Z-dienoic Acids with chain lengths between 12 and 20 carbons, as well as a series of 20-carbon 5-oxo fatty Acids, either fully saturated or containing between one and five double bonds. The effects of these compounds on neutrophils (calcium mobilization, CD11b expression, and cell migration) and eosinophils (actin polymerization) were compared with those of 5-oxo-ETE. The C12 and C14 analogs were without appreciable activity, whereas the C16 5-oxo-dienoic Acid was a weak partial agonist. In contrast, the corresponding C18 analog (5-oxo-18:2) was nearly as potent as 5-oxo-ETE. Among the C20 analogs, the fully saturated compound had virtually no activity, whereas 5-oxo-6E-eicosenoic Acid had only weak agonist activity. In contrast, 5-oxo-6E,8Z,11Z-eicosatrienoic Acid (5-oxo-20:3) and its 8-trans isomer were approximately equipotent with 5-oxo-ETE in activating granulocytes. Because of the potent effects of 5-oxo-20:3, we investigated its formation from Mead Acid (5Z,8Z,11Z-eicosatrienoic Acid), which accumulates in dietary essential fatty Acid deficiency, by neutrophils. The main Mead Acid metabolite identified was 5-hydroxy-6,8,11-eicosatrienoic Acid, followed by 5-oxo-20:3 and two 6-trans isomers of leukotriene B(3). We conclude that optimal activation of the OXE receptor is achieved with 5-oxo-ETE, 5-oxo-18:2, and 5-oxo-20:3, and that the latter compound could potentially be formed under conditions of essential fatty Acid deficiency.