Synthetic and structure/activity studies on acid-substituted 2- arylphenols: Discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5- hydroxyphenoxy]-propoxy]phenoxy]benzoic acid, a high-affinity leukotriene B4 receptor antagonist

Article abstract of DOI:10.1021/jm00022a006

Structural derivatives of LY255283 have been studied as receptor antagonists of leukotriene B₄. Substitution of the 2-hydroxyacetophenone subunit of 1 (LY255283) with a 2-arylphenol group provided entry into several new series that feature various mono- and diacidic core functionality. These new analogues, the subject of a broad structure-activity investigation, displayed significantly increased in vitro and in vive activity as receptor antagonists of LTB₄. A series of diaryl ether carboxylic acids demonstrated especially interesting activity and led to the discovery of compound 43b, 2- [2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]- propoxy]phenoxy]benzoic acid (LY293111), a 2-arylphenol-substituted diaryl ether carboxylic acid which displayed potent binding to human neutrophils (IC₅₀ = 17 ± 4.6 nM) and guinea pig lung membranes (IC₅₀ = 6.6 ± 0.71 nM), inhibition of LTB₄-induced expression of the CD11b/CD18 receptor on human neutrophils (IC₅₀ = 3.3 ± 0.81 nM), and inhibition of LTB₄-induced contraction of guinea pig lung parenchyma (pK(B) = 8.7 ± 0.16). In vivo, 43b demonstrated potent activity in inhibiting LTB₄-induced airway obstruction in the guinea pig when dosed by the oral (ED₅₀ = 0.40 mg/kg) or intravenous (ED₅₀ = 0.014 mg/kg) routes. A specific LTB₄ receptor antagonist, 43b had little effect on inhibiting contractions of guinea pig lung parenchyma induced by leukotriene D₄ (LTD₄), histamine, carbachol, or U46619. Compound 43b has been chosen as a clinical candidate and is currently in phase I studies for a variety of inflammatory diseases.