The Experts below are selected from a list of 15 Experts worldwide ranked by ideXlab platform
Zebala, John A. - One of the best experts on this subject based on the ideXlab platform.
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Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular MechanismS⃞
The American Society for Pharmacology and Experimental Therapeutics, 2026Co-Authors: Maeda, Dean Y., Quinn, Mark T., Schepetkin, Igor A., Kirpotina, Liliya N., Zebala, John A.Abstract:The chemokine receptors CXCR1/2 are involved in a variety of inflammatory diseases, including chronic obstructive pulmonary disease. Several classes of allosteric small-molecule CXCR1/2 antagonists have been developed. The data presented here describe the cellular pharmacology of the acid and Ester forms of the nicotinamide Glycolate pharmacophore, a potent antagonist of CXCR2 signaling by the chemokines CXCL1 and CXCL8. Ester forms of the nicotinamide Glycolate antagonized CXCL1-stimulated chemotaxis (IC50 = 42 nM) and calcium flux (IC50 = 48 nM) in human neutrophils, but they were inactive in cell-free assays of 125I-CXCL8/CXCR2 binding and CXCL1-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) exchange. Acid forms of the nicotinamide Glycolate were inactive in whole-cell assays of chemotaxis and calcium flux, but they inhibited 125I-CXCL8/CXCR2 binding and CXCL1-stimulated [35S]GTPγS exchange. The 3H Ester was internalized by neutrophils and rapidly converted to the 3H acid in a concentrative process. The 3H acid was not internalized by neutrophils but was sufficient alone to inhibit CXCL1-stimulated calcium flux in neutrophils that were permeabilized by electroporation to permit its direct access to the cell interior. Neutrophil efflux of the acid was probenecid-sensitive, consistent with an organic acid transporter. These data support a mechanism wherein the nicotinamide Glycolate Ester serves as a lipophilic precursor that efficiently translocates into the intracellular neutrophil space to liberate the active acid form of the pharmacophore, which then acts at an intracellular site. Rapid inactivation by plasma Esterases precluded use in vivo, but the mechanism elucidated provided insight for new nicotinamide pharmacophore classes with therapeutic potential
John A Zebala - One of the best experts on this subject based on the ideXlab platform.
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Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism
2020Co-Authors: □ S Dean, Y Maeda, Mark T Quinn, Igor A Schepetkin, Liliya N Kirpotina, John A ZebalaAbstract:ABSTRACT The chemokine receptors CXCR1/2 are involved in a variety of inflammatory diseases, including chronic obstructive pulmonary disease. Several classes of allosteric small-molecule CXCR1/2 antagonists have been developed. The data presented here describe the cellular pharmacology of the acid and Ester forms of the nicotinamide Glycolate pharmacophore, a potent antagonist of CXCR2 signaling by the chemokines CXCL1 and CXCL8. H acid was not internalized by neutrophils but was sufficient alone to inhibit CXCL1-stimulated calcium flux in neutrophils that were permeabilized by electroporation to permit its direct access to the cell interior. Neutrophil efflux of the acid was probenecid-sensitive, consistent with an organic acid transporter. These data support a mechanism wherein the nicotinamide Glycolate Ester serves as a lipophilic precursor that efficiently translocates into the intracellular neutrophil space to liberate the active acid form of the pharmacophore, which then acts at an intracellular site. Rapid inactivation by plasma Esterases precluded use in vivo, but the mechanism elucidated provided insight for new nicotinamide pharmacophore classes with therapeutic potential. Chemoattractant cytokines, or chemokines, promote the directed migration of polymorphonuclear leukocytes (PMNs) to sites of inflammation in a process known as chemotaxis. Among the most important chemokines released during inflammatory responses are the "Cys-XaaCys" (CXC) or ␣ chemokines, which are characterized by the presence of an intervening amino acid between con
Maeda, Dean Y. - One of the best experts on this subject based on the ideXlab platform.
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Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular MechanismS⃞
The American Society for Pharmacology and Experimental Therapeutics, 2026Co-Authors: Maeda, Dean Y., Quinn, Mark T., Schepetkin, Igor A., Kirpotina, Liliya N., Zebala, John A.Abstract:The chemokine receptors CXCR1/2 are involved in a variety of inflammatory diseases, including chronic obstructive pulmonary disease. Several classes of allosteric small-molecule CXCR1/2 antagonists have been developed. The data presented here describe the cellular pharmacology of the acid and Ester forms of the nicotinamide Glycolate pharmacophore, a potent antagonist of CXCR2 signaling by the chemokines CXCL1 and CXCL8. Ester forms of the nicotinamide Glycolate antagonized CXCL1-stimulated chemotaxis (IC50 = 42 nM) and calcium flux (IC50 = 48 nM) in human neutrophils, but they were inactive in cell-free assays of 125I-CXCL8/CXCR2 binding and CXCL1-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) exchange. Acid forms of the nicotinamide Glycolate were inactive in whole-cell assays of chemotaxis and calcium flux, but they inhibited 125I-CXCL8/CXCR2 binding and CXCL1-stimulated [35S]GTPγS exchange. The 3H Ester was internalized by neutrophils and rapidly converted to the 3H acid in a concentrative process. The 3H acid was not internalized by neutrophils but was sufficient alone to inhibit CXCL1-stimulated calcium flux in neutrophils that were permeabilized by electroporation to permit its direct access to the cell interior. Neutrophil efflux of the acid was probenecid-sensitive, consistent with an organic acid transporter. These data support a mechanism wherein the nicotinamide Glycolate Ester serves as a lipophilic precursor that efficiently translocates into the intracellular neutrophil space to liberate the active acid form of the pharmacophore, which then acts at an intracellular site. Rapid inactivation by plasma Esterases precluded use in vivo, but the mechanism elucidated provided insight for new nicotinamide pharmacophore classes with therapeutic potential
□ S Dean - One of the best experts on this subject based on the ideXlab platform.
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Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular Mechanism
2020Co-Authors: □ S Dean, Y Maeda, Mark T Quinn, Igor A Schepetkin, Liliya N Kirpotina, John A ZebalaAbstract:ABSTRACT The chemokine receptors CXCR1/2 are involved in a variety of inflammatory diseases, including chronic obstructive pulmonary disease. Several classes of allosteric small-molecule CXCR1/2 antagonists have been developed. The data presented here describe the cellular pharmacology of the acid and Ester forms of the nicotinamide Glycolate pharmacophore, a potent antagonist of CXCR2 signaling by the chemokines CXCL1 and CXCL8. H acid was not internalized by neutrophils but was sufficient alone to inhibit CXCL1-stimulated calcium flux in neutrophils that were permeabilized by electroporation to permit its direct access to the cell interior. Neutrophil efflux of the acid was probenecid-sensitive, consistent with an organic acid transporter. These data support a mechanism wherein the nicotinamide Glycolate Ester serves as a lipophilic precursor that efficiently translocates into the intracellular neutrophil space to liberate the active acid form of the pharmacophore, which then acts at an intracellular site. Rapid inactivation by plasma Esterases precluded use in vivo, but the mechanism elucidated provided insight for new nicotinamide pharmacophore classes with therapeutic potential. Chemoattractant cytokines, or chemokines, promote the directed migration of polymorphonuclear leukocytes (PMNs) to sites of inflammation in a process known as chemotaxis. Among the most important chemokines released during inflammatory responses are the "Cys-XaaCys" (CXC) or ␣ chemokines, which are characterized by the presence of an intervening amino acid between con
Kirpotina, Liliya N. - One of the best experts on this subject based on the ideXlab platform.
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Nicotinamide Glycolates Antagonize CXCR2 Activity through an Intracellular MechanismS⃞
The American Society for Pharmacology and Experimental Therapeutics, 2026Co-Authors: Maeda, Dean Y., Quinn, Mark T., Schepetkin, Igor A., Kirpotina, Liliya N., Zebala, John A.Abstract:The chemokine receptors CXCR1/2 are involved in a variety of inflammatory diseases, including chronic obstructive pulmonary disease. Several classes of allosteric small-molecule CXCR1/2 antagonists have been developed. The data presented here describe the cellular pharmacology of the acid and Ester forms of the nicotinamide Glycolate pharmacophore, a potent antagonist of CXCR2 signaling by the chemokines CXCL1 and CXCL8. Ester forms of the nicotinamide Glycolate antagonized CXCL1-stimulated chemotaxis (IC50 = 42 nM) and calcium flux (IC50 = 48 nM) in human neutrophils, but they were inactive in cell-free assays of 125I-CXCL8/CXCR2 binding and CXCL1-stimulated guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) exchange. Acid forms of the nicotinamide Glycolate were inactive in whole-cell assays of chemotaxis and calcium flux, but they inhibited 125I-CXCL8/CXCR2 binding and CXCL1-stimulated [35S]GTPγS exchange. The 3H Ester was internalized by neutrophils and rapidly converted to the 3H acid in a concentrative process. The 3H acid was not internalized by neutrophils but was sufficient alone to inhibit CXCL1-stimulated calcium flux in neutrophils that were permeabilized by electroporation to permit its direct access to the cell interior. Neutrophil efflux of the acid was probenecid-sensitive, consistent with an organic acid transporter. These data support a mechanism wherein the nicotinamide Glycolate Ester serves as a lipophilic precursor that efficiently translocates into the intracellular neutrophil space to liberate the active acid form of the pharmacophore, which then acts at an intracellular site. Rapid inactivation by plasma Esterases precluded use in vivo, but the mechanism elucidated provided insight for new nicotinamide pharmacophore classes with therapeutic potential