(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

Article abstract of DOI:10.1021/jm00046a017

(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 leukocutes with a K(i) 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.