Document Detail

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.
MedLine Citation:
PMID:  7473568     Owner:  NLM     Status:  MEDLINE    
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.
J S Sawyer; N J Bach; S R Baker; R F Baldwin; P S Borromeo; S L Cockerham; J H Fleisch; P Floreancig; L L Froelich; W T Jackson
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  38     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1995 Oct 
Date Detail:
Created Date:  1995-12-26     Completed Date:  1995-12-26     Revised Date:  2004-11-17    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  4411-32     Citation Subset:  IM    
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
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MeSH Terms
Airway Obstruction / metabolism
Benzoates / chemical synthesis,  chemistry,  pharmacology*
Guinea Pigs
Leukotriene B4 / antagonists & inhibitors,  pharmacology
Lung / drug effects,  metabolism
Neutrophils / drug effects,  metabolism
Phenols / chemical synthesis,  chemistry,  pharmacology*
Receptors, Leukotriene B4 / antagonists & inhibitors*
Structure-Activity Relationship
Tetrazoles / chemistry,  pharmacology
Reg. No./Substance:
0/Benzoates; 0/Phenols; 0/Receptors, Leukotriene B4; 0/Tetrazoles; 117690-79-6/LY 255283; 71160-24-2/Leukotriene B4

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