SC-41930: An inhibitor of leukotriene B4-stimulated human neutrophil functions

Tsai, Bie Shung; Villani-Price, Doreen; Keith, Robert H.; Zemaitis, J. M.; Bauer, R. F.; Leonard, Reid J.; Djurić, Stevan W.; Shone, Robert L.

doi:10.1016/0090-6980(89)90048-8

Cited by 43 publications

(32 citation statements)

References 18 publications

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“…SC 41930 (7-(3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid) is a potent first generation LTB 4 receptor antagonist developed by Searle (Monsanto) which reportedly binds to high-affinity LTB 4 receptors [114,138]. Further development of the compound was discontinued based on its ability to inhibit N-formyl-l-methionyll-leucyl-l-phenylalanine (f-MLP)-induced superoxide release [139].…”

Section: Ltb 4 Receptor Antagonistsmentioning

confidence: 99%

Potential use of lipoxygenase inhibitors for cancer chemoprevention

Steele¹,

Holmes²,

Hawk³

et al. 2000

Expert Opinion on Investigational Drugs

161

170

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Increasing evidence suggests that lipoxygenase (LO)-catalysed metabolites have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO products have been found in breast tumours, colon cancers, lung, skin and prostate cancers, as well as in cells from patients with both acute and chronic leukaemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumour cell adhesion and regulation of apoptotic cell death. Agents that block LO catalytic activity may be effective in preventing cancer by interfering with signalling events needed for tumour growth. In the past ten years, pharmaceuticals agents that specifically inhibit the 5-LO metabolic pathway have been developed to treat inflammatory diseases such as asthma, arthritis and psoriasis. Some of these compounds possess anti-oxidant properties and may be effective in preventing cancer by blocking free radical-induced genetic damage or by preventing the metabolic activation of carcinogens. Other compounds may work by negatively modulating DNA synthesis. Pharmacological profiles of potential chemopreventive agents are compiled from enzyme assays, in vitro testing (e.g., cell proliferation inhibition in human cancer cells) and in vivo animal carcinogenesis models (e.g., N-methyl-N-nitrosourea-induced rat mammary cancer, benzo(a)pyrene-induced lung tumours in strain A/J mice and hormone-induced prostate tumours in rats). In this way, compounds are identified for chemoprevention trials in human subjects. Based on currently available data, it is expected that the prevention of lung and prostate cancer will be initially studied in human trials of LO inhibitors.

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Section: Ltb 4 Receptor Antagonistsmentioning

confidence: 99%

Potential use of lipoxygenase inhibitors for cancer chemoprevention

Steele¹,

Holmes²,

Hawk³

et al. 2000

Expert Opinion on Investigational Drugs

161

170

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“…Neutrophil degranulation was measured by quantitating the release of myeloperoxidase (MPO) induced by 100 nM LTB4. 26 Compound 11 inhibited LTB4-induced degranulation in a concentration-dependent manner with an IC50 of 271 ± 14 nM (mean ± SEM for four experiments). This potency in degranulation was similar to that of compound 11 in the LTB4-induced calcium mobilization functional assay (IC50 = 131 ± 23 nM).…”

Section: Resultsmentioning

confidence: 96%

(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4-methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic Acid and Related Compounds: High Affinity Leukotriene B4 Receptor Antagonists

Daines¹,

Chambers²,

Eggleston³

et al. 1994

J. Med. Chem.

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(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4- methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic acid (11, SB 201993) is a novel, potent LTB4 receptor antagonist. Compound 11 arose from a structure-activity study of a series of trisubstituted pyridines that demonstrated LTB4 receptor antagonist activity. The placement of an additional methylene unit in the sulfur containing chain linking the pyridine and benzoic acid moieties of lead compound 8 (K(i) = 80 nM) resulted in a greater than 10-fold increase in receptor affinity. Additionally, in this new series of compounds, the oxidation state of the sulfur was found to be critical to the activity, i.e., the sulfoxide and sulfone showed substantially lower affinity for the LTB4 receptor. Compound 11 competitively inhibits the binding of [3H]LTB4 to LTB4 receptors on human polymorphonuclear leukocytes with a Ki of 7.1 nM and blocks both the LTB4-induced calcium mobilization and the LTB4-induced degranulation responses in these cells with IC50 values of 131 and 271 nM, respectively. Compound 11 demonstrated oral LTB4 antagonist activity as well as topical antiinflammatory activity in the mouse.

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“…e methylation of SLIT2 was associated with the development and progression of hepatocellular carcinoma [25], dysplasia of pancreatic cystic neoplasms [26], breast cancer [27], and nasopharyngeal carcinoma [28]. e methylation of KDR was also correlated with the development and progression of oral squamous cell carcinoma [29].…”

Section: Discussionmentioning

confidence: 99%

Combined Analysis of the Aberrant Epigenetic Alteration of Pancreatic Ductal Adenocarcinoma

Huang

et al. 2019

BioMed Research International

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Background. Pancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal malignancies due to its high morbidity and mortality. DNA methylation exerts a vital part in the development of PDAC. However, a mechanistic role of mutual interactions between DNA methylation and mRNA as epigenetic regulators on transcriptomic alterations and its correlation with clinical outcomes such as survival have remained largely uncovered in cancer. Therefore, elucidation of aberrant epigenetic alteration in the development of PDAC is an urgent problem to be solved. In this work, we conduct an integrative epigenetic analysis of PDAC to identify aberrant DNA methylation-driven cancer genes during the occurrence of cancer. Methods. DNA methylation matrix and mRNA profile were obtained from the TCGA database. The integration of methylation and gene expression datasets was analyzed using an R package MethylMix. The genes with hypomethylation/hypermethylation were further validated in the Kaplan–Meier analysis. The correlation analysis of gene expression and aberrant DNA methylation was also conducted. We performed a pathway analysis on aberrant DNG methylation genes identified by MethylMix criteria using ConsensusPathDB. Results. 188 patients with both methylation data and mRNA data were considered eligible. A mixture model was constructed, and differential methylation genes in normal and tumor groups using the Wilcoxon rank test was performed. With the inclusion criteria, 95 differential methylation genes were detected. Among these genes, 74 hypermethylation and 21 hypomethylation genes were found. The pathway analysis revealed an increase in hypermethylation of genes involved in ATP-sensitive potassium channels, Robo4, and VEGF signaling pathways crosstalk, and generic transcription pathway. Conclusion. Integrated analysis of the aberrant epigenetic alteration in pancreatic ductal adenocarcinoma indicated that differentially methylated genes could play a vital role in the occurrence of PDAC by bioinformatics analysis. The present work can help clinicians to elaborate on the function of differentially methylated expressed genes and pathways in PDAC. CDO1, GJD2, ID4, NOL4, PAX6, TRIM58, and ZNF382 might act as aberrantly DNA-methylated biomarkers for early screening and therapy of PDAC in the future.

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SC-41930: An inhibitor of leukotriene B4-stimulated human neutrophil functions

Cited by 43 publications

References 18 publications

Potential use of lipoxygenase inhibitors for cancer chemoprevention

Potential use of lipoxygenase inhibitors for cancer chemoprevention

(E)-3-[[[[6-(2-Carboxyethenyl)-5-[[8-(4-methoxyphenyl)octyl]oxy]-2-pyridinyl]methyl]thio]methyl]benzoic Acid and Related Compounds: High Affinity Leukotriene B4 Receptor Antagonists

Combined Analysis of the Aberrant Epigenetic Alteration of Pancreatic Ductal Adenocarcinoma

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