The Experts below are selected from a list of 28191 Experts worldwide ranked by ideXlab platform
Lihu Yang - One of the best experts on this subject based on the ideXlab platform.
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Discovery of 3-piperidinyl-1-cyclopentanecarboxamide as a novel scaffold for highly potent CC chemokine Receptor 2 antagonists.
Journal of Medicinal Chemistry, 2007Co-Authors: Lihu Yang, Gabor Butora, Richard Jiao, Changyou Zhou, Sander G. Mills, Julia M. Ayala, Pasquale P. Vicario, William H. Parsons, Alex Pasternak, Margaret A. CascieriAbstract:Introduction of ring restrictions to a linear aminobutyramide CC chemokine Receptor 2 (CCR2) antagonist lead (2) led to the discovery of a 1,3-disubstituted cyclopentane scaffold with enhanced hCCR2 Receptor binding and antagonist activity. (1S,3R)-N-[3,5-Bis(trifluoromethyl)benzyl]-1-methyl-3-[(1R,3‘R)-methyl-1‘H-spiro[indene-1,4‘-piperidin]-1‘-yl]cyclopentanecarboxamide (16) had IC50 of 1.3 nM (binding) and 0.45 nM (functional chemotaxis) against hCCR2. It also showed activity against the mouse CCR2 Receptor with an IC50 of 130 nM. Compound 16 is selective against other chemokine Receptors, including CCR5 (∼500-fold).
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α-Aminothiazole-γ-aminobutanoic amides as potent, small molecule CCR2 Receptor antagonists
Bioorganic & medicinal chemistry letters, 2006Co-Authors: Changyou Zhou, Sander G. Mills, Malcolm Maccoss, Pasquale P. Vicario, Liangqin Guo, William H. Parsons, Margaret A. Cascieri, Hans J. Zweerink, Martin S. Springer, Lihu YangAbstract:Abstract A series of racemic and homochiral α-aminothiazole-γ-aminobutyroamides that display high affinities for human and murine CCR2 and functional antagonism by inhibition of monocyte recruitment are described. A representative example is (2S)-2-[2-(acetylamino)-1,3-thiazol-4-yl]-N-[3-methyl-5-(trifluoromethyl)benzyl]-4-(4-phenylpiperidin-1-yl)butanamide, which shows 5 nM affinity for human monocytes and CHO cells expressing the human CCR2b Receptor. It also inhibited MCP-1 initiated chemotaxis of human monocytes with an IC50 of 0.69 nM.
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4-Amino-2-alkyl-butyramides as small molecule CCR2 antagonists with favorable pharmacokinetic properties
Bioorganic & medicinal chemistry letters, 2006Co-Authors: Gabor Butora, Shankaran Kothandaraman, Alexander Pasternak, Gregori J. Morriello, Malcolm Maccoss, Pasquale P. Vicario, William H. Parsons, Margaret A. Cascieri, Deodialsingh Guiadeen, Lihu YangAbstract:Abstract A systematic examination of the central aromatic portion of the lead (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(1′H-spiro[indene-1,4′-piperidin]-1′-yl)butanamide (9) led to the discovery of a novel class of CCR2 Receptor antagonists, which carry small alicyclic groups such as cyclopropyl, cylobutyl, or cyclopropylmethyl attached at C2 of the carbon backbone. The most potent compound discovered, namely (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-[(1R,3′R)-3′-methyl-1′H-spiro[indene-1,4′-piperidin]-1′-yl]butanamide (29), showed very high binding affinity (IC50 = 4 nM, human monocyte) and excellent selectivity toward other related chemokine Receptors. The excellent pharmacokinetic profile of this new lead compound allows for extensive in vivo evaluation.
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Discovery of 3,5-bis(trifluoromethyl)benzyl L-arylglycinamide based potent CCR2 antagonists.
Bioorganic & medicinal chemistry letters, 2006Co-Authors: Lihu Yang, Gabor Butora, Alexander Pasternak, Gregori J. Morriello, Changyou Zhou, Sander G. Mills, Malcolm Maccoss, Liangqin Guo, William H. Parsons, Pasquale P. VicarioAbstract:Abstract Systematic modification of a screening lead yielded a class of potent glycinamide based CCR2 antagonists. The best compound (55, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-{[2-(1-piperidinyl)ethyl]amino}-2-(3-thienyl)acetamide) displayed good binding affinity (IC50 = 30 and 39 nM) toward human monocytes and CHO cell expressing human CCR2b, respectively. Functionally, it blocked MCP-1 (CCL2)-induced calcium mobilization (IC50 = 50 nM) and chemotaxis mediated through the CCR2 Receptor (9.6 nM). It is selective against other chemokine Receptors tested.
Anna Mondino - One of the best experts on this subject based on the ideXlab platform.
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The soluble D2D388-274 fragment of the urokinase Receptor inhibits monocyte chemotaxis and integrin-dependent cell adhesion
Journal of Cell Science, 2004Co-Authors: Federico Furlan, Simone Orlando, Carlo Laudanna, Massimo Resnati, Veronica Basso, Francesco Blasi, Anna MondinoAbstract:We have previously shown that chymotrypsin-cleaved soluble uPAR (D2D3 88-274 ) elicits migration of monocytic cells through interaction with FPRL-1, a G protein-coupled Receptor that is homologous to the fMLP Receptor. Here, we report that D2D3 88-274 also modulates the ability of monocytes to migrate in response to other chemokines. Pretreatment of monocytes with increasing amounts of D2D3 88-274 prevents cell migration in response to MCP-1, RANTES and fMLP. We demonstrate that D2D3 88-274 does not inhibit MCP-1 Receptor binding, elicit CCR2 internalization and prevent MCP-1-induced intracellular Ca 2+ increase. Thus, CCR2 Receptor desensitization cannot account for D2D3 88-274 -mediated inhibition of MCP-1-induced cell migration. Rather, we show that pretreatment of monocytes with D2D3 88-274 dramatically decreases chemokine-induced integrin-dependent rapid cell adhesion by interacting with FPRL-1. Together, our results indicate that chemokine-dependent cell migration can be regulated not only by homologous and heterologous Receptor desensitization, but also by inhibition of integrin-dependent cell adhesion, an important step in cell transmigration.
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The soluble D2D3(88-274) fragment of the urokinase Receptor inhibits monocyte chemotaxis and integrin-dependent cell adhesion.
Journal of cell science, 2004Co-Authors: Federico Furlan, Simone Orlando, Carlo Laudanna, Massimo Resnati, Veronica Basso, Francesco Blasi, Anna MondinoAbstract:We have previously shown that chymotrypsin-cleaved soluble uPAR (D2D3(88-274)) elicits migration of monocytic cells through interaction with FPRL-1, a G protein-coupled Receptor that is homologous to the fMLP Receptor. Here, we report that D2D3(88-274) also modulates the ability of monocytes to migrate in response to other chemokines. Pretreatment of monocytes with increasing amounts of D2D3(88-274) prevents cell migration in response to MCP-1, RANTES and fMLP. We demonstrate that D2D3(88-274) does not inhibit MCP-1 Receptor binding, elicit CCR2 internalization and prevent MCP-1-induced intracellular Ca(2+) increase. Thus, CCR2 Receptor desensitization cannot account for D2D3(88-274)-mediated inhibition of MCP-1-induced cell migration. Rather, we show that pretreatment of monocytes with D2D3(88-274) dramatically decreases chemokine-induced integrin-dependent rapid cell adhesion by interacting with FPRL-1. Together, our results indicate that chemokine-dependent cell migration can be regulated not only by homologous and heterologous Receptor desensitization, but also by inhibition of integrin-dependent cell adhesion, an important step in cell transmigration.
Ronald P. Gladue - One of the best experts on this subject based on the ideXlab platform.
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CCR2 Receptor blockade alters blood monocyte subpopulations but does not affect atherosclerotic lesions in apoe mice
Atherosclerosis, 2010Co-Authors: Robert J. Aiello, Bret D. Perry, Patricia-ann Bourassa, Andrew Robertson, Weifan Weng, Delvin R. Knight, Andrew H. Smith, Kosea S. Frederick, Amit S. Kalgutkar, Ronald P. GladueAbstract:Abstract Objective The CCR2 Receptor plays a crucial role in monocyte recruitment and has been implicated as a contributing factor to atherosclerosis. CCR2 Receptor deletion leads to significant inhibition of lesion development. Our objective was to determine if CCR2 Receptor blockade with a small molecule would have a beneficial effect of decreasing established lesions. Methods and results We demonstrated that CCR2 blockade had no significant effect on advanced lesions or the progression of fatty streaks. CCR2 blockade in mice resulted in elevations in plasma CCL2 levels and a significant reduction in the plasma Ly-6C hi subpopulations of monocytes expressing the CCR2 Receptor. Neither CCL2 elevation nor margination of the Ly-6C hi population was observed in CCR2 −/− mice. Conclusions CCR2 Receptor blockade with a small molecule antagonist at dose levels showing efficacy in several inflammatory models did not show a beneficial effect in murine models of atherosclerosis. Elevations in CCL2 and margination of Ly-6C hi cells demonstrate that the role of CCR2 in controlling monocyte levels goes beyond the control of monocyte emigration.
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CCR2 Receptor blockade alters blood monocyte subpopulations but does not affect atherosclerotic lesions in apoE(-/-) mice.
Atherosclerosis, 2009Co-Authors: Robert J. Aiello, Bret D. Perry, Patricia-ann Bourassa, Andrew Robertson, Weifan Weng, Delvin R. Knight, Andrew H. Smith, Kosea S. Frederick, Amit S. Kalgutkar, Ronald P. GladueAbstract:Abstract Objective The CCR2 Receptor plays a crucial role in monocyte recruitment and has been implicated as a contributing factor to atherosclerosis. CCR2 Receptor deletion leads to significant inhibition of lesion development. Our objective was to determine if CCR2 Receptor blockade with a small molecule would have a beneficial effect of decreasing established lesions. Methods and results We demonstrated that CCR2 blockade had no significant effect on advanced lesions or the progression of fatty streaks. CCR2 blockade in mice resulted in elevations in plasma CCL2 levels and a significant reduction in the plasma Ly-6C hi subpopulations of monocytes expressing the CCR2 Receptor. Neither CCL2 elevation nor margination of the Ly-6C hi population was observed in CCR2 −/− mice. Conclusions CCR2 Receptor blockade with a small molecule antagonist at dose levels showing efficacy in several inflammatory models did not show a beneficial effect in murine models of atherosclerosis. Elevations in CCL2 and margination of Ly-6C hi cells demonstrate that the role of CCR2 in controlling monocyte levels goes beyond the control of monocyte emigration.
Anna M Aragay - One of the best experts on this subject based on the ideXlab platform.
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Signaling pathways for monocyte chemoattractant protein 1-mediated extracellular signal-regulated kinase activation.
Molecular pharmacology, 2003Co-Authors: M. Carmen Jiménez-sainz, Federico Mayor, Beate Fast, Anna M AragayAbstract:G protein-coupled Receptors (GPCRs) initiate diverse down-stream signaling events in response to ligand stimulation, as rapid activation of the extracellular signal-regulated kinase ERK1 and ERK2. The chemokine monocyte chemoattractant protein-1 (MCP-1) is the agonist for several chemokine Receptors that belong to the GPCR superfamily, CCR2 being the most important. Stimulation of mitogen-activated protein kinases (MAPKs) by MCP-1 has been implicated in integrin activation and chemotaxis, but the molecular pathways down-stream of the Receptors remain unclear. To dissect the cascade of events leading to MAPK activation upon CCR2 Receptor stimulation, several specific inhibitors and mutants of signal transduction proteins were used in monocytic cells endogenously expressing CCR2 and/or in human embryonic kidney-293 cells transfected with CCR2B Receptors and epitope-tagged ERK1. We show that ERK activation by MCP-1 involves heterotrimeric Gi protein subunits, protein kinase C, phosphoinositide-3-kinase, and Ras. On the other hand, the activity of cytosolic tyrosine kinases, epidermal growth factor Receptor transactivation, or variations in intracellular calcium levels are not required for the mitogenic activation elicited by MCP-1. In addition, we find that internalization of CCR2B itself is not necessary for efficient MCP-1-induced activation of ERK, although a dynamin mutant partially inhibits ERK stimulation. These results suggest that different parallel pathways are being activated that lead to the full activation of the mitogen-activated protein kinase cascade and that internalization of other signaling proteins but not of the Receptor is required for complete ERK activation.
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the chemokine monocyte chemotactic protein 1 triggers janus kinase 2 activation and tyrosine phosphorylation of the CCR2b Receptor
Journal of Immunology, 1998Co-Authors: Mario Mellado, Jose Miguel Rodriguezfrade, Anna M Aragay, G Del Real, Antonio J Vilacoro, Ana Martín, Federico Mayor, Antonio Serrano, Carlos MartinezaAbstract:The chemokines are a growing family of low m.w., 70- to 80-residue proinflammatory cytokines that operate by interacting with G protein-coupled Receptors. Chemokines are involved in cell migration and in the activation of specific leukocyte subsets. Using the Mono Mac 1 monocytic cell line, we show that monocyte chemotactic protein 1 (MCP-1) triggers activation of the Janus kinase 2 (JAK2)/STAT3 pathway and CCR2 Receptor tyrosine phosphorylation. Both Ca 2+ mobilization and cell migration are blocked in Mono Mac 1 cells by tyrphostin B42, a specific JAK2 kinase inhibitor. Within seconds of MCP-1 activation, JAK2 phosphorylates CCR2 at the Tyr 139 position and promotes JAK2/STAT3 complex association to the Receptor. This MCP-1-initiated phosphorylation and association to JAK2 is also observed in CCR2B-transfected HEK293 cells. In contrast, when a CCR2B Tyr 139 Phe mutant is expressed in HEK293 cells, it is not phosphorylated in tyrosine and triggers neither JAK2/STAT3 activation nor Ca 2+ mobilization in response to MCP-1. These results implicate the tyrosine kinase pathway in early chemokine signaling, suggesting a key role for this kinase in later events.
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Monocyte chemoattractant protein-1-induced CCR2B Receptor desensitization mediated by the G protein-coupled Receptor kinase 2
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Anna M Aragay, Mario Mellado, José María Frade, Carlos Martínez-a, Martin A, M. C. Jimenez-sainz, Federico MayorAbstract:Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 Receptors, which are members of the G protein-coupled Receptor family. MCP-1 plays a critical role in both activation and migration of leukocytes. Rapid chemokine Receptor desensitization is very likely essential for accurate chemotaxis. In this report, we show that MCP-1 binding to the CCR2 Receptor in Mono Mac 1 cells promotes the rapid desensitization of MCP-1-induced calcium flux responses. This desensitization correlates with the Ser/Thr phosphorylation of the Receptor and with the transient translocation of the G protein-coupled Receptor kinase 2 (GRK2, also called β-adrenergic kinase 1 or βARK1) to the membrane. We also demonstrate that GRK2 and the uncoupling protein β-arrestin associate with the Receptor, forming a macromolecular complex shortly after MCP-1 binding. Calcium flux responses to MCP-1 in HEK293 cells expressing the CCR2B Receptor were also markedly reduced upon cotransfection with GRK2 or the homologous kinase GRK3. Nevertheless, expression of the GRK2 dominant-negative mutant βARK-K220R did not affect the initial calcium response, but favored Receptor response to a subsequent challenge by agonists. The modulation of the CCR2B Receptor by GRK2 suggests an important role for this kinase in the regulation of monocyte and lymphocyte response to chemokines.
Federico Mayor - One of the best experts on this subject based on the ideXlab platform.
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Signaling pathways for monocyte chemoattractant protein 1-mediated extracellular signal-regulated kinase activation.
Molecular pharmacology, 2003Co-Authors: M. Carmen Jiménez-sainz, Federico Mayor, Beate Fast, Anna M AragayAbstract:G protein-coupled Receptors (GPCRs) initiate diverse down-stream signaling events in response to ligand stimulation, as rapid activation of the extracellular signal-regulated kinase ERK1 and ERK2. The chemokine monocyte chemoattractant protein-1 (MCP-1) is the agonist for several chemokine Receptors that belong to the GPCR superfamily, CCR2 being the most important. Stimulation of mitogen-activated protein kinases (MAPKs) by MCP-1 has been implicated in integrin activation and chemotaxis, but the molecular pathways down-stream of the Receptors remain unclear. To dissect the cascade of events leading to MAPK activation upon CCR2 Receptor stimulation, several specific inhibitors and mutants of signal transduction proteins were used in monocytic cells endogenously expressing CCR2 and/or in human embryonic kidney-293 cells transfected with CCR2B Receptors and epitope-tagged ERK1. We show that ERK activation by MCP-1 involves heterotrimeric Gi protein subunits, protein kinase C, phosphoinositide-3-kinase, and Ras. On the other hand, the activity of cytosolic tyrosine kinases, epidermal growth factor Receptor transactivation, or variations in intracellular calcium levels are not required for the mitogenic activation elicited by MCP-1. In addition, we find that internalization of CCR2B itself is not necessary for efficient MCP-1-induced activation of ERK, although a dynamin mutant partially inhibits ERK stimulation. These results suggest that different parallel pathways are being activated that lead to the full activation of the mitogen-activated protein kinase cascade and that internalization of other signaling proteins but not of the Receptor is required for complete ERK activation.
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the chemokine monocyte chemotactic protein 1 triggers janus kinase 2 activation and tyrosine phosphorylation of the CCR2b Receptor
Journal of Immunology, 1998Co-Authors: Mario Mellado, Jose Miguel Rodriguezfrade, Anna M Aragay, G Del Real, Antonio J Vilacoro, Ana Martín, Federico Mayor, Antonio Serrano, Carlos MartinezaAbstract:The chemokines are a growing family of low m.w., 70- to 80-residue proinflammatory cytokines that operate by interacting with G protein-coupled Receptors. Chemokines are involved in cell migration and in the activation of specific leukocyte subsets. Using the Mono Mac 1 monocytic cell line, we show that monocyte chemotactic protein 1 (MCP-1) triggers activation of the Janus kinase 2 (JAK2)/STAT3 pathway and CCR2 Receptor tyrosine phosphorylation. Both Ca 2+ mobilization and cell migration are blocked in Mono Mac 1 cells by tyrphostin B42, a specific JAK2 kinase inhibitor. Within seconds of MCP-1 activation, JAK2 phosphorylates CCR2 at the Tyr 139 position and promotes JAK2/STAT3 complex association to the Receptor. This MCP-1-initiated phosphorylation and association to JAK2 is also observed in CCR2B-transfected HEK293 cells. In contrast, when a CCR2B Tyr 139 Phe mutant is expressed in HEK293 cells, it is not phosphorylated in tyrosine and triggers neither JAK2/STAT3 activation nor Ca 2+ mobilization in response to MCP-1. These results implicate the tyrosine kinase pathway in early chemokine signaling, suggesting a key role for this kinase in later events.
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Monocyte chemoattractant protein-1-induced CCR2B Receptor desensitization mediated by the G protein-coupled Receptor kinase 2
Proceedings of the National Academy of Sciences of the United States of America, 1998Co-Authors: Anna M Aragay, Mario Mellado, José María Frade, Carlos Martínez-a, Martin A, M. C. Jimenez-sainz, Federico MayorAbstract:Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine cytokine family, whose physiological function is mediated by binding to the CCR2 and CCR4 Receptors, which are members of the G protein-coupled Receptor family. MCP-1 plays a critical role in both activation and migration of leukocytes. Rapid chemokine Receptor desensitization is very likely essential for accurate chemotaxis. In this report, we show that MCP-1 binding to the CCR2 Receptor in Mono Mac 1 cells promotes the rapid desensitization of MCP-1-induced calcium flux responses. This desensitization correlates with the Ser/Thr phosphorylation of the Receptor and with the transient translocation of the G protein-coupled Receptor kinase 2 (GRK2, also called β-adrenergic kinase 1 or βARK1) to the membrane. We also demonstrate that GRK2 and the uncoupling protein β-arrestin associate with the Receptor, forming a macromolecular complex shortly after MCP-1 binding. Calcium flux responses to MCP-1 in HEK293 cells expressing the CCR2B Receptor were also markedly reduced upon cotransfection with GRK2 or the homologous kinase GRK3. Nevertheless, expression of the GRK2 dominant-negative mutant βARK-K220R did not affect the initial calcium response, but favored Receptor response to a subsequent challenge by agonists. The modulation of the CCR2B Receptor by GRK2 suggests an important role for this kinase in the regulation of monocyte and lymphocyte response to chemokines.