(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
| Autor: | 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 |
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| Rok vydání: | 1994 |
| Předmět: |
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 |
| Zdroj: | Journal of Medicinal Chemistry. 37:3327-3336 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00046a017 |
| Popis: | (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. |
| Databáze: | OpenAIRE |
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