Document Detail


Inhibition of cytosolic phospholipase A2alpha: hit to lead optimization.
MedLine Citation:
PMID:  16392799     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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
Related Documents :
2726859 - Mechanism-based analysis of enzyme inhibitors of amide bond hydrolysis.
24237419 - Copper-transporting atpase is important for malaria parasite fertility.
11576619 - Substrate interaction with 5alpha-reductase enzyme: influence of the 17beta-chain chira...
19668859 - Design, synthesis and biological evaluation of sugar-derived esters, alpha-ketoesters a...
10821719 - Structure-activity study on the in vitro antiprotozoal activity of glutathione derivati...
20024979 - 5-benzylidenethiazolidin-4-ones as multitarget inhibitors of bacterial mur ligases.
10354519 - Clostridium perfringens beta-toxin is sensitive to thiol-group modification but does no...
18571929 - Discovery of aminoquinolines as a new class of potent inhibitors of heat shock protein ...
19854649 - Discovery of highly potent and selective type i b-raf kinase inhibitors.
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    
Affiliation:
Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA. jmckew@wyeth.com
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line
Cell Proliferation / drug effects
Cytosol / enzymology
Drug Design*
Drug Evaluation, Preclinical
Enzyme Inhibitors / chemical synthesis*,  chemistry,  pharmacology*
Group IV Phospholipases A2
Humans
Indoles / chemical synthesis*,  chemistry,  pharmacology*
Male
Molecular Structure
Phospholipases A / antagonists & inhibitors*
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Indoles; EC 3.1.1.-/Phospholipases A; EC 3.1.1.4/Group IV Phospholipases A2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  Synthesis and in vivo validation of [O-methyl-11C]2-{4-[4-(7-methoxynaphthalen-1-yl)piperazin- 1-yl]...
Next Document:  Structure-activity relationships at the 5-position of thiolactomycin: an intact (5R)-isoprene unit i...