SYNTHETIC AND STRUCTURE-ACTIVITY STUDIES ON ACID-SUBSTITUTED 2-ARYLPHENOLS - DISCOVERY OF OPHENYL)-5-HYDROXYPHENOXY]-PROPOXY]PHENOXY]BENZOIC ACID, A HIGH-AFFINITY LEUKOTRIENE B-4 RECEPTOR ANTAGONIST

Structural derivatives of LY255283 have been studied as receptor antag onists of leukotriene B-4. Substitution of the 2-hydroxyacetophenone s ubunit of 1 (LY255283) with a 2-arylphenol group provided entry into s everal new series that feature various mono- and diacidic core functio nality. These new analogues, the subject of a broad structure-activity investigation, displayed significantly increased in vitro and in vivo activity as receptor antagonists of LTB(4). A series of diaryl ether carboxylic acids demonstrated especially interesting activity and led to the discovery of compound 43b, -[3-[2-ethyl-4-(4-fluorophenyl)-5-hy droxyphenoxy]- propoxy]phenoxy]benzoic acid (LY293111), a 2-arylphenol -substituted diaryl ether carboxylic acid which displayed potent bindi ng to human neutrophils (IC50 = 17 +/- 14.6 nM) and guinea pig lung me mbranes (IC50 6.6 +/- 0.71 nM), inhibition of LTB(4)-induced expressio n of the CD11b/CD18 receptor on human neutrophils (IC50 - 3.3 +/- 0.81 nM), and inhibition of LTB(4)-induced contraction of guinea pig lung parenchyma (pK(B) = 8.7 +/- 0.16). In vivo, 43b demonstrated potent ac tivity in inhibiting LTB(4)-induced airway obstruction in the guinea p ig when dosed by the oral (ED(50) = 0.40 mg/kg) or intravenous (ED(50) = 0.014 mg/kg) routes. A specific LTB(4) receptor antagonist, 43b had little effect on inhibiting contractions of guinea pig lung parenchym a induced by leukotriene D-4 (LTD(4)), histamine, carbachol, or U46619 . Compound 43b has been chosen as a clinical candidate and is currentl y in phase I studies for a variety of inflammatory diseases.