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
| Autor: | Sandra L. Cockerham, Larry L. Froelich, Baker, Baldwin Rf, Jason Scott Sawyer, Bach Nicholas J, Jerome H. Fleisch, William T. Jackson, P. S. Borromeo, Floreancig Paul Edward |
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| Rok vydání: | 1995 |
| Předmět: |
Stereochemistry
medicine.drug_class Leukotriene B4 Neutrophils Carboxylic acid Guinea Pigs Receptors Leukotriene B4 Tetrazoles Benzoates Guinea pig chemistry.chemical_compound Structure-Activity Relationship Phenols In vivo Drug Discovery medicine Animals Humans Lung Benzoic acid chemistry.chemical_classification Leukotriene B4 receptor Receptor antagonist Airway Obstruction chemistry Molecular Medicine Histamine |
| Zdroj: | Journal of medicinal chemistry. 38(22) |
| ISSN: | 0022-2623 |
| Popis: | 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 (IC 50 = 17 ± 4.6 nM) and guinea pig lung membranes (IC 50 = 6.6 ± 0.71 nM), inhibition of LTB 4 -induced expression of the CD11b/CD18 receptor on human neutrophils (IC 50 = 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. |
| Databáze: | OpenAIRE |
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