(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
| العنوان: | (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 |
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| المؤلفون: | R A, Daines, P A, Chambers, D S, Eggleston, J J, Foley, D E, Griswold, R C, Haltiwanger, D R, Jakas, W D, Kingsbury, L D, Martin, I, Pendrak |
| المصدر: | Journal of Medicinal Chemistry. 37:3327-3336 |
| بيانات النشر: | American Chemical Society (ACS), 1994. |
| سنة النشر: | 1994 |
| مصطلحات موضوعية: | Neutrophils, Pyridines, medicine.drug_class, Stereochemistry, Carboxylic acid, Receptors, Leukotriene B4, Thio, Crystallography, X-Ray, Cytoplasmic Granules, Benzoates, Binding, Competitive, Leukotriene B4, Sulfone, Structure-Activity Relationship, chemistry.chemical_compound, Drug Discovery, medicine, Humans, Benzoic acid, chemistry.chemical_classification, Molecular Structure, Chemistry, Sulfoxide, Biological activity, respiratory system, Receptor antagonist, Molecular Medicine, Calcium, lipids (amino acids, peptides, and proteins), Receptor antagonist activity |
| الوصف: | (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. |
| تدمد: | 1520-4804 0022-2623 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::49b1deca0554311ece95c563c1e51085 https://doi.org/10.1021/jm00046a017 |
| رقم الأكسشن: | edsair.doi.dedup.....49b1deca0554311ece95c563c1e51085 |
| قاعدة البيانات: | OpenAIRE |
Find this issue from the American Chemical Society | تدمد: | 15204804 00222623 |
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