The Experts below are selected from a list of 159 Experts worldwide ranked by ideXlab platform
Christopher J. Hawkey - One of the best experts on this subject based on the ideXlab platform.
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Low dose aspirin: selective inhibition of rectal dialysis Thromboxane B2 in healthy volunteers.
Alimentary Pharmacology & Therapeutics, 2007Co-Authors: A.t. Cole, B. Filipowicz, P. Hyman‐taylor, Christopher J. HawkeyAbstract:SUMMARY Aim: To investigate the degree and selectivity of rectal Thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet Thromboxane to rectal Thromboxane. Methods: The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of Thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B2 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of Thromboxane B2, leukotriene B4, prostaglandin E2, and serum Thromboxane B2 were measured by radioimmunoassay. Results: Dialysate Thromboxane B, levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95 % CI:0.79–1.43 ng/ml) on placebo, by 29% (95% CI: 11–40%) to 0.75 ng/ml(0.56–1.01 ng/ml) (P= 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E, was 1.47 ng/ml (0.97–2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leultotriene B, was 0.45 ng/ml(0.34–0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum Thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95 % by plain aspirin 300 mg, and by 82 % by enteric coated aspirin 300 mg, respectively (P < 0.01). These results show that 29 % of the rectal Thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4, is inhibited by low dose aspirin. We infer that 34% of the rectal Thromboxane B2 is platelet-derived in our volunteers. Conclusion: Low dose aspirin will selectively inhibit a proportion of rectal Thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.
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Low dose aspirin: selective inhibition of rectal dialysis Thromboxane B2 in healthy volunteers.
Alimentary Pharmacology & Therapeutics, 2007Co-Authors: A.t. Cole, B. Filipowicz, P. Hyman‐taylor, Christopher J. HawkeyAbstract:SUMMARY Aim: To investigate the degree and selectivity of rectal Thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet Thromboxane to rectal Thromboxane. Methods: The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of Thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B2 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of Thromboxane B2, leukotriene B4, prostaglandin E2, and serum Thromboxane B2 were measured by radioimmunoassay. Results: Dialysate Thromboxane B, levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95 % CI:0.79–1.43 ng/ml) on placebo, by 29% (95% CI: 11–40%) to 0.75 ng/ml(0.56–1.01 ng/ml) (P= 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E, was 1.47 ng/ml (0.97–2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leultotriene B, was 0.45 ng/ml(0.34–0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum Thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95 % by plain aspirin 300 mg, and by 82 % by enteric coated aspirin 300 mg, respectively (P < 0.01). These results show that 29 % of the rectal Thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4, is inhibited by low dose aspirin. We infer that 34% of the rectal Thromboxane B2 is platelet-derived in our volunteers. Conclusion: Low dose aspirin will selectively inhibit a proportion of rectal Thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.
Graham P. Pidgeon - One of the best experts on this subject based on the ideXlab platform.
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Examination of Thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer
Molecular Cancer, 2011Co-Authors: Mary-clare Cathcart, Kathy Gately, Kenneth J. O'byrne, Robert Cummins, Graham P. PidgeonAbstract:Background: Thromboxane synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
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examination of Thromboxane synthase as a prognostic factor and therapeutic target in non small cell lung cancer
Molecular Cancer, 2011Co-Authors: Mary-clare Cathcart, Kathy Gately, Kenneth J Obyrne, Robert Cummins, Graham P. PidgeonAbstract:Thromboxane synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
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examination of Thromboxane synthase as a prognostic factor and therapeutic target in non small cell lung cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2011Co-Authors: Mary-clare Cathcart, Kathy Gately, Kenneth J Obyrne, Robert Cummins, Graham P. PidgeonAbstract:Background: Thromboxane synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB 2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB 2levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC. © 2011 Cathcart et al; licensee BioMed Central Ltd.
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Thromboxane Synthase and Prostate Cancer Progression
2004Co-Authors: Kenneth V. Honn, David J Grignon, Graham P. Pidgeon, Mario LambertiAbstract:Abstract : The initiation and progression of prostate cancer remain not well understood to enable development of interventional therapy. Thromboxane synthase is an enzyme downstream of cyclooxygenase, utilizing prostaglandin H to form Thromboxane A2. Using immunohistochemistry analysis, we found that 25% of clinical prostate tumor specimens had strong expression of Thromboxane synthase; 33% of cases had medium expression and 42% of cases had weak expression of Thromboxane synthase. Prostate cancer cells isolated from lymph node metastasis had higher levels of Thromboxane synthase expression and activity than those isolated from the primary tumor sites in an animal model. We cloned and sequenced full-length Thromboxane synthase cDNA from PC-3 cells and constructed an expression vector. Increased expression of Thromboxane synthase in DU145 cells was found to stimulate cell migration. Inhibition of Thromboxane synthase or blockade of Thromboxane A2 function inhibited prostate cancer cell migration. Further we found that PCa cells express receptors for TXA2 and stimulation with TXA2 mimetic led to the activation of RhoA and cell retraction. Our study suggest that Thromboxane synthase and its eicosanoid product play a contributory role in prostate cancer progression.
A.t. Cole - One of the best experts on this subject based on the ideXlab platform.
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Low dose aspirin: selective inhibition of rectal dialysis Thromboxane B2 in healthy volunteers.
Alimentary Pharmacology & Therapeutics, 2007Co-Authors: A.t. Cole, B. Filipowicz, P. Hyman‐taylor, Christopher J. HawkeyAbstract:SUMMARY Aim: To investigate the degree and selectivity of rectal Thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet Thromboxane to rectal Thromboxane. Methods: The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of Thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B2 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of Thromboxane B2, leukotriene B4, prostaglandin E2, and serum Thromboxane B2 were measured by radioimmunoassay. Results: Dialysate Thromboxane B, levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95 % CI:0.79–1.43 ng/ml) on placebo, by 29% (95% CI: 11–40%) to 0.75 ng/ml(0.56–1.01 ng/ml) (P= 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E, was 1.47 ng/ml (0.97–2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leultotriene B, was 0.45 ng/ml(0.34–0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum Thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95 % by plain aspirin 300 mg, and by 82 % by enteric coated aspirin 300 mg, respectively (P < 0.01). These results show that 29 % of the rectal Thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4, is inhibited by low dose aspirin. We infer that 34% of the rectal Thromboxane B2 is platelet-derived in our volunteers. Conclusion: Low dose aspirin will selectively inhibit a proportion of rectal Thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.
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Low dose aspirin: selective inhibition of rectal dialysis Thromboxane B2 in healthy volunteers.
Alimentary Pharmacology & Therapeutics, 2007Co-Authors: A.t. Cole, B. Filipowicz, P. Hyman‐taylor, Christopher J. HawkeyAbstract:SUMMARY Aim: To investigate the degree and selectivity of rectal Thromboxane inhibition by low dose aspirin and there by investigate the contribution of platelet Thromboxane to rectal Thromboxane. Methods: The study was a randomized double-blind placebo controlled crossover study. Twelve healthy volunteers were studied, each over four separate study periods with two weeks wash-out between each period. Changes in levels of Thromboxane (TX) B2, prostaglandin (PG) E2 and leukotriene (LT) B2 in rectal dialysates were measured in response to 5 days oral low dose aspirin therapy in one of three once-daily formulations (plain 75 mg, plain 300 mg or enteric coated 300 mg), and compared to placebo. For each study period, rectal dialysates (4 h duration) were obtained at baseline and twice more after 5 days of aspirin or placebo therapy. Dialysate levels of Thromboxane B2, leukotriene B4, prostaglandin E2, and serum Thromboxane B2 were measured by radioimmunoassay. Results: Dialysate Thromboxane B, levels were consistently inhibited by low dose aspirin (overall results of all formulations, 75 to 300 mg daily) from 1.06 ng/ml (geometric mean, 95 % CI:0.79–1.43 ng/ml) on placebo, by 29% (95% CI: 11–40%) to 0.75 ng/ml(0.56–1.01 ng/ml) (P= 0.046) on aspirin. In the absence of aspirin the level of prostaglandin E, was 1.47 ng/ml (0.97–2.23 ng/ml) and in the presence of aspirin was not significantly changed. The dialysate level of leultotriene B, was 0.45 ng/ml(0.34–0.61 ng/ml) in the absence of aspirin and there was no significant change on low dose aspirin. Serum Thromboxane was inhibited by 80% to 20% of placebo values by plain aspirin 75 mg, by 95 % by plain aspirin 300 mg, and by 82 % by enteric coated aspirin 300 mg, respectively (P < 0.01). These results show that 29 % of the rectal Thromboxane, but none of the rectal prostaglandin E2 or leukotriene B4, is inhibited by low dose aspirin. We infer that 34% of the rectal Thromboxane B2 is platelet-derived in our volunteers. Conclusion: Low dose aspirin will selectively inhibit a proportion of rectal Thromboxane and may have prophylactic therapeutic potential in inflammatory bowel disease.
Mary-clare Cathcart - One of the best experts on this subject based on the ideXlab platform.
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examination of Thromboxane synthase as a prognostic factor and therapeutic target in non small cell lung cancer
Molecular Cancer, 2011Co-Authors: Mary-clare Cathcart, Kathy Gately, Kenneth J Obyrne, Robert Cummins, Graham P. PidgeonAbstract:Thromboxane synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
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Examination of Thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer
Molecular Cancer, 2011Co-Authors: Mary-clare Cathcart, Kathy Gately, Kenneth J. O'byrne, Robert Cummins, Graham P. PidgeonAbstract:Background: Thromboxane synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.
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examination of Thromboxane synthase as a prognostic factor and therapeutic target in non small cell lung cancer
Faculty of Health; Institute of Health and Biomedical Innovation, 2011Co-Authors: Mary-clare Cathcart, Kathy Gately, Kenneth J Obyrne, Robert Cummins, Graham P. PidgeonAbstract:Background: Thromboxane synthase (TXS) metabolises prostaglandin H2 into Thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB 2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB 2levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting Thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC. © 2011 Cathcart et al; licensee BioMed Central Ltd.
John Steele - One of the best experts on this subject based on the ideXlab platform.
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Thromboxane modulating agents. 3. 1H-imidazol-1-ylalkyl- and 3-pyridinylalkyl-substituted 3-[2-[(arylsulfonyl)amino]ethyl]benzenepropanoic acid derivatives as dual Thromboxane synthase inhibitor/Thromboxane receptor antagonists.
Journal of Medicinal Chemistry, 1997Co-Authors: Roger Peter Dickinson, Kevin Neil Dack, Clive J. Long, John SteeleAbstract:The design of a series of dual Thromboxane synthase inhibitor/Thromboxane receptor antagonists based on a 3-[2-[(arylsulfonyl)amino]ethyl]benzenepropanoic acid Thromboxane receptor antagonist template is described. Introduction of a 5-(1H-imidazol-1-ylmethyl), a 5-(3-pyridinylmethyl), or a 5-(3-pyridinyloxy) substituent leads to dual agents with Thromboxane synthase inhibitory activity comparable with that of dazmegrel (7). In addition, 3-pyridinylalkyl substituents also make a significant contribution to Thromboxane receptor binding. Oral administration of compound 74 (5 mg/kg) to conscious dogs produces long-lasting Thromboxane synthase inhibition and Thromboxane receptor blockade as measured by inhibition of U46619-induced platelet aggregation ex vivo.
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Thromboxane modulating agents. 1. Design of 1-[(arylsulfonyl)amino] alkylindole derivatives as dual Thromboxane synthase inhibitor/Thromboxane receptor antagonists.
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: Roger Peter Dickinson, Kevin Neil Dack, John SteeleAbstract:Abstract The design of a series of dual Thromboxane synthase inhibitor/Thromboxane receptor antagonists based on an indole Thromboxane synthase inhibitor template is described. The indole-5-propanoic acid derivatives 17, 22 and 23 were found to be potent dual agents in vitro.
