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Sylvain Doré - One of the best experts on this subject based on the ideXlab platform.
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Abstract TMP51: Activation of PGE2 EP1 Receptor Promotes Microglial Phagocytosis Though CD36 Receptor Recycling
Stroke, 2016Co-Authors: Jason Day, Harrison Phillips, Bryan Slootsky, Sylvain DoréAbstract:Background and Purpose: We have shown that the deletion of prostaglandin E2 (PGE2) EP1 Receptor undermined microglial phagocytosis in vivo. However, the related mechanism still remains unknown. CD36 is a type II scavenger Receptor that mediates microglial phagocytosis. It was reported that microglial CD36 contributes to hematoma clearance after intracerebral hemorrhage (ICH). In this study, we sought to identify the effects of two EP1 agonists on microglial phagocytosis and CD36 Receptor recycling in primary microglial cultures. Method: The EP1 agonists: 17-phenyl trinor-PGE2 (17-pt-PGE2) and ONO-DI-004 were used to treat primary microglial cultures, respectively. Fluorescent latex beads or CFSE-labeled red blood cells (CFSE-RBCs) were added to microglial cells at a concentration of ten beads/RBCs per cell for live-cell imaging. Immunocytochemistry was also performed with antibody against ionized calcium-binding adapter molecule 1 (Iba1, a marker to microglia). Furthermore, we analyzed CD36 Receptor recycling by using an established Receptor recycling assay. Result: The primary microglial cells were incubated with fluorescent latex beads and treated with the EP1 agonist 17-pt-PGE2 for 120 min. We found that 17-pt-PGE2 significantly increased the number of attached beads to microglial cells at the concentration of 10 μM from 40 min to 120 min of incubation. Furthermore, we analyzed CD36 Receptor recycling using an established Receptor recycling assay and the quantitative results showed that 10 μM of 17-pt-PGE2 treatment markedly increased the area of recycled CD36 Receptor in microglial cells. We then treated primary microglial cells with another selective EP1 agonist ONO-DI-004 for 120 min at the concentration of 5 μM and 10 μM, respectively. The area of CFSE-RBCs after ice-cold PBS washing was markedly increased with 10 μM of ONO-DI-004 treatment. In the live-cell imaging experiment, 10 μM of ONO-DI-004 treatment also significantly increased the number of attached CFSE-RBCs to microglial cells from 25 min to 60 min of incubation. Conclusions: This study showed that the EP1 agonists: 17-pt-PGE2 and ONO-DI-004 can promote microglial phagocytosis in vitro and enhanced CD36 Receptor recycling could mediate some of these effects.
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detrimental role of the EP1 prostanoid Receptor in blood brain barrier damage following experimental ischemic stroke
Scientific Reports, 2015Co-Authors: Sylvain Doré, Abdullah Shafique Ahmad, Jenna L Leclerc, Jan C Frankowski, Kelly M Demars, Kimberly E Hawkins, Changjun Yang, Eduardo CandelariojalilAbstract:Cyclooxygenase-2 (COX-2) is activated in response to ischemia and significantly contributes to the neuroinflammatory process. Accumulation of COX-2-derived prostaglandin E2 (PGE2) parallels the substantial increase in stroke-mediated blood-brain barrier (BBB) breakdown. Disruption of the BBB is a serious consequence of ischemic stroke, and is mainly mediated by matrix metalloproteinases (MMPs). This study aimed to investigate the role of PGE2 EP1 Receptor in neurovascular injury in stroke. We hypothesized that pharmacological blockade or genetic deletion of EP1 protects against BBB damage and hemorrhagic transformation by decreasing the levels and activity of MMP-3 and MMP-9. We found that post-ischemic treatment with the EP1 antagonist, SC-51089, or EP1 genetic deletion results in a significant reduction in BBB disruption and reduced hemorrhagic transformation in an experimental model of transient focal cerebral ischemia. These neurovascular protective effects of EP1 inactivation are associated with a significant reduction in MMP-9/-3, less peripheral neutrophil infiltration, and a preservation of tight junction proteins (ZO-1 and occludin) composing the BBB. Our study identifies the EP1 signaling pathway as an important link between neuroinflammation and MMP-mediated BBB breakdown in ischemic stroke. Targeting the EP1 Receptor could represent a novel approach to diminish the devastating consequences of stroke-induced neurovascular damage.
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Intracerebral hemorrhage outcomes following selective blockade or stimulation of the PGE2 EP1 Receptor
BMC neuroscience, 2015Co-Authors: Jenna L Leclerc, Abdullah Shafique Ahmad, Nilendra Singh, Luke Soshnik-schierling, Ellis Greene, Alex Dang, Sylvain DoréAbstract:Inflammation following intracerebral hemorrhage (ICH) significantly contributes to secondary brain damage and poor outcomes. Prostaglandin E2 (PGE2) is known to modulate neuroinflammatory responses and is upregulated in response to brain injury as a result of changes in inducible cyclooxygenase 2 (COX-2) and the membrane-bound type of PGE synthase. Inhibition of COX-2 activity has been reported to attenuate ICH-induced brain injury; however, the clinical utility of such drugs is limited due to the potential for severe side effects. Therefore, it is now important to search for downstream targets capable of preferentially modulating PGE2 signaling, and the four E prostanoid Receptors, EP1-4, which are the main targets of PGE2, remain a viable therapeutic option. We have previously shown that EP1 Receptor deletion aggravates ICH-induced brain injury and impairs functional recovery, thus the current study aimed to elaborate on these results by including a pharmacologic approach targeting the EP1 Receptor. Chronic post-treatment with the selective EP1 Receptor antagonist, SC-51089, increased lesion volume by 30.1 ± 14.5% (p
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intracerebral hemorrhage outcomes following selective blockade or stimulation of the pge2 EP1 Receptor
BMC Neuroscience, 2015Co-Authors: Jenna L Leclerc, Abdullah Shafique Ahmad, Nilendra Singh, Ellis Greene, Alex Dang, Luke Soshnikschierling, Sylvain DoréAbstract:Inflammation following intracerebral hemorrhage (ICH) significantly contributes to secondary brain damage and poor outcomes. Prostaglandin E2 (PGE2) is known to modulate neuroinflammatory responses and is upregulated in response to brain injury as a result of changes in inducible cyclooxygenase 2 (COX-2) and the membrane-bound type of PGE synthase. Inhibition of COX-2 activity has been reported to attenuate ICH-induced brain injury; however, the clinical utility of such drugs is limited due to the potential for severe side effects. Therefore, it is now important to search for downstream targets capable of preferentially modulating PGE2 signaling, and the four E prostanoid Receptors, EP1-4, which are the main targets of PGE2, remain a viable therapeutic option. We have previously shown that EP1 Receptor deletion aggravates ICH-induced brain injury and impairs functional recovery, thus the current study aimed to elaborate on these results by including a pharmacologic approach targeting the EP1 Receptor. Chronic post-treatment with the selective EP1 Receptor antagonist, SC-51089, increased lesion volume by 30.1 ± 14.5% (p < 0.05) and treatment with the EP1 agonist, 17-pt-PGE2, improved neuromuscular functional recovery on grip strength (p < 0.01) and hanging wire (p < 0.05) behavioral testing. To begin identifying the mechanisms involved in EP1-mediated neuroprotection after ICH, histology was performed to assess ferric iron content, neuroinflammation, leukocyte transendothelial migratory potential, and peripheral neutrophil and immunoglobulin infiltration. Following ICH, mice treated with the antagonist displayed increased ferric iron (p < 0.05) and cortical microgliosis (p < 0.05), whereas treatment with the agonist decreased cortical (p < 0.01) and striatal (p < 0.001) astrogliosis, leukocyte transendothelial migratory potential (p < 0.01), neutrophil infiltration (p < 0.05), and blood brain barrier breakdown (p < 0.05). In agreement with our previous results, selective antagonism of the EP1 Receptor aggravated ICH-induced brain injury. Furthermore, EP1 Receptor agonism improved anatomical outcomes and functional recovery. Thus, the present data continues to reinforce a putative role for EP1 as a new and more selective therapeutic target for the treatment of ICH that could reduce the side effects associated with COX-2 inhibition while still exploiting the beneficial effects.
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Abstract W P260: Role of the Prostaglandin E2 EP1 Receptor in Traumatic Brain Injury
Stroke, 2015Co-Authors: Alexander V. Glushakov, Shuh Narumiya, Jawad A. Fazal, Sylvain DoréAbstract:Introduction: Brain injuries promote upregulation of so-called proinflammatory prostaglandin E2 leading to overactivation of a class of its cognate G-protein coupled Receptors, notably EP1, which is considered as a promising target for treatment of ischemic stroke and, possibly, other neurological disorders involving excitotoxicity. However, our recent data suggest that of EP1 Receptor in intracerebral hemorrhage may play a protective role. The goal of this study was to investigate a translational potential of EP1 Receptor for treatment of traumatic brain injury (TBI). Methods: The acute brain injury was induced using controlled cortical impact (CCI) in wildtype (WT) and genetic EP1 Receptor knockout mice (EP1-/-). Neurological deficit scores (NDS) and anatomical brain pathology were accessed at 48h after injury. Results: CCI resulted in significant cortical lesions, localized hippocampal edema and neurological deficits compared to animals from sham group underwent craniotomy only. The NDS after CCI were ...
Adrian Hall - One of the best experts on this subject based on the ideXlab platform.
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discovery of sodium 6 5 chloro 2 4 chloro 2 fluorophenyl methyl oxy phenyl methyl 2 pyridinecarboxylate gsk269984a an EP1 Receptor antagonist for the treatment of inflammatory pain
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Mairi Gibson, Andy Billinton, Nicholas Maughan Clayton, Paul Goldsmith, David N. Hurst, Alan NaylorAbstract:Abstract We describe the medicinal chemistry programme that led to the identification of the EP1 Receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP1 antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
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Discovery of sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (GSK269984A) an EP1 Receptor antagonist for the treatment of inflammatory pain
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Mairi Gibson, Andy Billinton, Nicholas Maughan Clayton, Paul Goldsmith, David N. Hurst, Alan NaylorAbstract:Abstract We describe the medicinal chemistry programme that led to the identification of the EP1 Receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP1 antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
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Discovery of brain penetrant, soluble, pyrazole amide EP1 Receptor antagonists.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Andy Billinton, Paul Goldsmith, Thomas George Christopher Hayhow, Alan K. Bristow, Leanne Cutler, Ian R. KilfordAbstract:Abstract We describe the discovery of a series of pyrazole amide EP1 Receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1–2.0:1 in addition to good solubility and metabolic stability.
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Non-acidic pyrazole EP1 Receptor antagonists with in vivo analgesic efficacy.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Andy Billinton, Nicholas Maughan Clayton, Paul Goldsmith, Thomas George Christopher Hayhow, David N. Hurst, Ian R. KilfordAbstract:Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP1 Receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
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Discovery of a novel indole series of EP1 Receptor antagonists by scaffold hopping.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Alan Naylor, Andy Billinton, Paul Goldsmith, David N. Hurst, Sadhana Patel, Tiziana ScoccittiAbstract:Abstract We describe the medicinal chemistry approach that generated a novel indole series of EP1 Receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain.
Xiao-ming Bai - One of the best experts on this subject based on the ideXlab platform.
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prostaglandin e2 stimulates β1 integrin expression in hepatocellular carcinoma through the EP1 Receptor pkc nf κb pathway
Scientific Reports, 2015Co-Authors: Xiao-ming Bai, Li Zhang, Jie Wang, Yan Guo, Jinshun Pan, Qinyi Yang, Min Zhang, Feng Shi, Wei Shu, Yipin WangAbstract:Prostaglandin E 2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 Receptor/PKC/NF-κB pathway
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Prostaglandin E2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 Receptor/PKC/NF-κB pathway.
Scientific reports, 2014Co-Authors: Xiao-ming Bai, Li Zhang, Jie Wang, Yan Guo, Jinshun Pan, Qinyi Yang, Min Zhang, Feng ShiAbstract:Prostaglandin E 2 stimulates β1-integrin expression in hepatocellular carcinoma through the EP1 Receptor/PKC/NF-κB pathway
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Prostaglandin E2 upregulates β1 integrin expression via the E prostanoid 1 Receptor/nuclear factor κ‑light‑chain‑enhancer of activated B cells pathway in non‑small‑cell lung cancer cells
Molecular medicine reports, 2014Co-Authors: Xiao-ming Bai, Li Zhang, Jie Wang, Qinyi Yang, Min Zhang, Wei Shu, Shukai Xia, Shanyu Cheng, Yipin WangAbstract:The prostaglandin E2 (PGE2) E prostanoid (EP)1 Receptor shown to be associated with lung cancer cell invasion. However, the mechanism of EP1 Receptor-mediated cell migration remains to be elucidated. β1 integrin is an essential regulator of the tumorigenic properties of non-small-cell lung carcinoma (NSCLC) cells. To date, little is known regarding the association between the EP1 Receptor and β1 integrin expression. The present study investigated the effect of EP1 Receptor activation on β1 integrin expression and cell migration in NSCLC cells. A total of 34 patients with clinical diagnosis of NSCLC and 10 patients with benign disease were recruited for the present study. The expression levels of the EP1 Receptor and β1 integrin expression were studied in resected lung tissue using immunohistochemistry. A statistical analysis was performed using Stata se12.0 software. The effects of PGE2, EP1 agonist 17-phenyl trinor-PGE2 (17-PT-PGE2) and the nuclear factor κ-B (NF-κB) inhibitor on β1 integrin expression were investigated on A549 cells. The expression of β1 integrin and the phosphorylation of NF-κB‑p65 Ser536 was investigated by western blot analysis. Cell migration was assessed by a transwell assay. The results demonstrated that β1 integrin and EP1 Receptor expression exhibited a positive correlation of evident significance in the 44 samples. The in vitro migration assay revealed that cell migration was increased by 30% when the cells were treated with 5 µM 17-PT-PGE2 and that the pre-treatment of β1 integrin monoclonal antibody inhibited 17-PT-PGE2‑mediated cell migration completely. PGE2 and 17-PT-PGE2 treatment increased β1 integrin expression. RNA interference against the EP1 Receptor blocked the PGE2-mediated β1 integrin expression in A549 cells. Treatment with 17-PT-PGE2 induced NF-κB activation, and the selective NF-κB inhibitor pyrrolidinedithiocarbamate inhibited 17-PT-PGE2-mediated β1 integrin expression. In conclusion, the present study indicated that the PGE2 EP1 Receptor regulates β1 integrin expression and cell migration in NSCLC cells by activating the NF-κB signaling pathway. Targeting the PGE2/EP1/β1 integrin signaling pathway may aid in the development of new therapeutic strategies for the prevention and treatment of this type of cancer.
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prostaglandin e Receptor EP1 mediated phosphorylation of focal adhesion kinase enhances cell adhesion and migration in hepatocellular carcinoma cells
International Journal of Oncology, 2013Co-Authors: Xiao-ming Bai, Li Zhang, Hai Zhang, Jie Wang, Yan Guo, Min Zhang, Rong Rong, Shukai Xia, Shanyu Cheng, Wei ShuAbstract:The prostaglandin E₂ (PGE₂) EP1 Receptor has been implicated in hepatocellular carcinoma (HCC) cell invasion. However, little is known about the mechanisms of EP1 Receptor-mediated cell adhesion and migration. We previously showed that PGE₂ promotes cell adhesion and migration by activating focal adhesion kinase (FAK). The present study was designed to elucidate the association between the EP1 Receptor and FAK activation in HCC cells and to investigate the related signaling pathways. The effects of PGE₂, EP1 agonist 17-phenyl trinor-PGE₂ (17-PT-PGE₂), PKC and EGFR inhibitors on FAK activation were investigated by treatment of Huh-7 cells. Phosphorylation of FAK Y397 and c-Src Y416 was investigated by western blotting. Cell adhesion and migration were analyzed by WST and transwell assays, respectively. Protein kinase C (PKC) activity was measured with a PKC assay kit. The results showed that 17-PT-PGE₂ (3 µM) increased FAK Y397 phosphorylation by more than 2-fold and promoted cell adhesion and migration in Huh-7 cells. In transfected 293 cells, expression of the EP1 Receptor was confirmed to upregulate FAK phosphorylation, while the EP1 Receptor antagonist sc-19220 decreased PGE₂-mediated FAK activation. PKC activity and c-Src Y416 phosphorylation were enhanced after 17-PT-PGE₂ treatment. Both PKC and c-Src inhibitor suppressed the 17-PT-PGE₂-upregulated FAK phosphorylation, as well as 17-PT-PGE₂-induced cell adhesion and migration. In addition, exogenous epidermal growth factor (EGF) treatment increased FAK phosphorylation. The EGF Receptor (EGFR) inhibitor also suppressed 17-PT-PGE₂-upregulated FAK phosphorylation. Our study suggests that the PGE₂ EP1 Receptor regulates FAK phosphorylation by activating the PKC/c-Src and EGFR signal pathways, which may coordinately regulate adhesion and migration in HCC.
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Prostaglandin E₂ Receptor EP1-mediated phosphorylation of focal adhesion kinase enhances cell adhesion and migration in hepatocellular carcinoma cells.
International journal of oncology, 2013Co-Authors: Xiao-ming Bai, Li Zhang, Hai Zhang, Jie Wang, Yan Guo, Min Zhang, Shukai Xia, Rong RongAbstract:The prostaglandin E₂ (PGE₂) EP1 Receptor has been implicated in hepatocellular carcinoma (HCC) cell invasion. However, little is known about the mechanisms of EP1 Receptor-mediated cell adhesion and migration. We previously showed that PGE₂ promotes cell adhesion and migration by activating focal adhesion kinase (FAK). The present study was designed to elucidate the association between the EP1 Receptor and FAK activation in HCC cells and to investigate the related signaling pathways. The effects of PGE₂, EP1 agonist 17-phenyl trinor-PGE₂ (17-PT-PGE₂), PKC and EGFR inhibitors on FAK activation were investigated by treatment of Huh-7 cells. Phosphorylation of FAK Y397 and c-Src Y416 was investigated by western blotting. Cell adhesion and migration were analyzed by WST and transwell assays, respectively. Protein kinase C (PKC) activity was measured with a PKC assay kit. The results showed that 17-PT-PGE₂ (3 µM) increased FAK Y397 phosphorylation by more than 2-fold and promoted cell adhesion and migration in Huh-7 cells. In transfected 293 cells, expression of the EP1 Receptor was confirmed to upregulate FAK phosphorylation, while the EP1 Receptor antagonist sc-19220 decreased PGE₂-mediated FAK activation. PKC activity and c-Src Y416 phosphorylation were enhanced after 17-PT-PGE₂ treatment. Both PKC and c-Src inhibitor suppressed the 17-PT-PGE₂-upregulated FAK phosphorylation, as well as 17-PT-PGE₂-induced cell adhesion and migration. In addition, exogenous epidermal growth factor (EGF) treatment increased FAK phosphorylation. The EGF Receptor (EGFR) inhibitor also suppressed 17-PT-PGE₂-upregulated FAK phosphorylation. Our study suggests that the PGE₂ EP1 Receptor regulates FAK phosphorylation by activating the PKC/c-Src and EGFR signal pathways, which may coordinately regulate adhesion and migration in HCC.
Gerard M.p. Giblin - One of the best experts on this subject based on the ideXlab platform.
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discovery of sodium 6 5 chloro 2 4 chloro 2 fluorophenyl methyl oxy phenyl methyl 2 pyridinecarboxylate gsk269984a an EP1 Receptor antagonist for the treatment of inflammatory pain
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Mairi Gibson, Andy Billinton, Nicholas Maughan Clayton, Paul Goldsmith, David N. Hurst, Alan NaylorAbstract:Abstract We describe the medicinal chemistry programme that led to the identification of the EP1 Receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP1 antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
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Discovery of sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (GSK269984A) an EP1 Receptor antagonist for the treatment of inflammatory pain
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Mairi Gibson, Andy Billinton, Nicholas Maughan Clayton, Paul Goldsmith, David N. Hurst, Alan NaylorAbstract:Abstract We describe the medicinal chemistry programme that led to the identification of the EP1 Receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP1 antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
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Discovery of brain penetrant, soluble, pyrazole amide EP1 Receptor antagonists.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Andy Billinton, Paul Goldsmith, Thomas George Christopher Hayhow, Alan K. Bristow, Leanne Cutler, Ian R. KilfordAbstract:Abstract We describe the discovery of a series of pyrazole amide EP1 Receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1–2.0:1 in addition to good solubility and metabolic stability.
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Non-acidic pyrazole EP1 Receptor antagonists with in vivo analgesic efficacy.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Andy Billinton, Nicholas Maughan Clayton, Paul Goldsmith, Thomas George Christopher Hayhow, David N. Hurst, Ian R. KilfordAbstract:Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP1 Receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
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Discovery of a novel indole series of EP1 Receptor antagonists by scaffold hopping.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Alan Naylor, Andy Billinton, Paul Goldsmith, David N. Hurst, Sadhana Patel, Tiziana ScoccittiAbstract:Abstract We describe the medicinal chemistry approach that generated a novel indole series of EP1 Receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain.
Susan H. Brown - One of the best experts on this subject based on the ideXlab platform.
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discovery of sodium 6 5 chloro 2 4 chloro 2 fluorophenyl methyl oxy phenyl methyl 2 pyridinecarboxylate gsk269984a an EP1 Receptor antagonist for the treatment of inflammatory pain
Bioorganic & Medicinal Chemistry Letters, 2009Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Mairi Gibson, Andy Billinton, Nicholas Maughan Clayton, Paul Goldsmith, David N. Hurst, Alan NaylorAbstract:Abstract We describe the medicinal chemistry programme that led to the identification of the EP1 Receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP1 antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
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Discovery of sodium 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylate (GSK269984A) an EP1 Receptor antagonist for the treatment of inflammatory pain
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Mairi Gibson, Andy Billinton, Nicholas Maughan Clayton, Paul Goldsmith, David N. Hurst, Alan NaylorAbstract:Abstract We describe the medicinal chemistry programme that led to the identification of the EP1 Receptor antagonist GSK269984A (8h). GSK269984A was designed to overcome development issues encountered with previous EP1 antagonists such as GW848687X and was found to display excellent activity in preclinical models of inflammatory pain. However, upon cross species pharmacokinetic profiling, GSK269984A was predicted to have suboptimal human pharmacokinetic and was thus progressed to a human microdose study.
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Discovery of brain penetrant, soluble, pyrazole amide EP1 Receptor antagonists.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Andy Billinton, Paul Goldsmith, Thomas George Christopher Hayhow, Alan K. Bristow, Leanne Cutler, Ian R. KilfordAbstract:Abstract We describe the discovery of a series of pyrazole amide EP1 Receptor antagonists with good aqueous solubility and CNS penetration. In order to achieve solubility we investigated the incorporation of a basic group in the region of the molecule previously occupied by a carboxylic acid, which was known to be a key element of the pharmacophore. This study led to the identification of compounds such as 4h, 4j and 10b which demonstrated brain-to-blood ratios of 0.8:1–2.0:1 in addition to good solubility and metabolic stability.
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Non-acidic pyrazole EP1 Receptor antagonists with in vivo analgesic efficacy.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Andy Billinton, Nicholas Maughan Clayton, Paul Goldsmith, Thomas George Christopher Hayhow, David N. Hurst, Ian R. KilfordAbstract:Replacement of the carboxylic acid group in a series of previously described methylene-linked pyrazole EP1 Receptor antagonists led to the discovery of amide, reversed amide and carbamate derivatives. Two compounds, 10a and 10b, were identified as brain penetrant compounds and both demonstrated efficacy in the CFA model of inflammatory pain.
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Discovery of a novel indole series of EP1 Receptor antagonists by scaffold hopping.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Adrian Hall, Susan H. Brown, Anita Chowdhury, Gerard M.p. Giblin, Alan Naylor, Andy Billinton, Paul Goldsmith, David N. Hurst, Sadhana Patel, Tiziana ScoccittiAbstract:Abstract We describe the medicinal chemistry approach that generated a novel indole series of EP1 Receptor antagonists. The SAR of this new template was evaluated and culminated in the identification of compound 12g which demonstrated in vivo efficacy in a preclinical model of inflammatory pain.