Document Detail

Inhibition of cytosolic phospholipase A2alpha: hit to lead optimization.
MedLine Citation:
PMID:  16392799     Owner:  NLM     Status:  MEDLINE    
Compound 1 was previously reported to be a potent inhibitor of cPLA(2)alpha in both artificial monomeric substrate and cell-based assays. However, 1 was inactive in whole blood assays previously used to characterize cyclooxygenase and lipoxygenase inhibitors. The IC(50) of 1 increased dramatically with cell number or lipid/detergent concentration. In an attempt to insert an electrophilic ketone between the indole and benzoic acid moieties, we discovered that increasing the distance between the two moieties gave a compound with activity in the GLU (7-hydroxycoumarinyl-gamma-linolenate) micelle assay, which contains lipid and detergent. Extensive structure-activity relationship work around this lead identified a potent pharmacophore for cPLA(2)alpha inhibition. The IC(50)s between the GLU micelle and rat whole blood assays correlated highly. No correlation was found for other parameters, including lipophilicity or acidity of the required acid functionality. Compounds 25, 39, and 94 emerged as potent, selective inhibitors of cPLA(2)alpha and represent well-validated starting points for further optimization.
John C McKew; Megan A Foley; Paresh Thakker; Mark L Behnke; Frank E Lovering; Fuk-Wah Sum; Steve Tam; Kun Wu; Marina W H Shen; Wen Zhang; Mario Gonzalez; Shanghao Liu; Anu Mahadevan; Howard Sard; Soo Peang Khor; James D Clark
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  49     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2006 Jan 
Date Detail:
Created Date:  2006-01-05     Completed Date:  2006-02-16     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  135-58     Citation Subset:  IM    
Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA.
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MeSH Terms
Cell Line
Cell Proliferation / drug effects
Cytosol / enzymology
Drug Design*
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis*,  chemistry,  pharmacology*
Group IV Phospholipases A2
Indoles / chemical synthesis*,  chemistry,  pharmacology*
Molecular Structure
Phospholipases A / antagonists & inhibitors*
Rats, Sprague-Dawley
Structure-Activity Relationship
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Indoles; EC 3.1.1.-/Phospholipases A; EC IV Phospholipases A2

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