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.
J Med Chem
; 38(22): 4411-32, 1995 Oct 27.
Article
en En
| MEDLINE
| ID: mdl-7473568
ABSTRACT
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 vivo 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 (pKB = 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.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenoles
/
Benzoatos
/
Receptores de Leucotrieno B4
Límite:
Animals
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
1995
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA