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 B-4 RECEPTOR ANTAGONIST

• Published in: Journal of medicinal chemistry Vol. 38; no. 22; pp. 4411 - 4432
• Main Authors: SAWYER, JS, BACH, NJ, BAKER, BALDWIN, RF, BORROMEO, PS, COCKERHAM, SL, FLEISCH, JH, FLOREANCIG, P, FROELICH, LL, JACKSON, WT, MARDER, P, PALKOWITZ, JA, ROMAN, CR, SAUSSY, DL, SCHMITTLING, EA, SILBAUGH, SA, SPAETHE, SM, STENGEL, PW, SOFIA, MJ
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 27.10.1995
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; POLYMORPHONUCLEAR LEUKOCYTE RECEPTORS; LY255283; POTENT; LTB RECEPTOR; GUINEA-PIG; HYDROXYACETOPHENONES; BINDING; DERIVATIVES; BRONCHOALVEOLAR LAVAGE; BRONCHIAL-ASTHMA
• ISSN: 0022-2623
• DOI: 10.1021/jm00022a006

Structural derivatives of LY255283 have been studied as receptor antagonists of leukotriene B-4. 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 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, 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 +/- 14.6 nM) and guinea pig lung membranes (IC50 6.6 +/- 0.71 nM), inhibition of LTB(4)-induced expression 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 activity in inhibiting LTB(4)-induced airway obstruction in the guinea pig 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 parenchyma induced by leukotriene D-4 (LTD(4)), 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.