%0 Journal Article
%A McKew, John C.
%A Foley, Megan A.
%A Thakker, Paresh
%A Behnke, Mark L.
%A Lovering, Frank E.
%A Sum, Fuk-Wah
%A Tam, Steve
%A Wu, Kun
%A W. H. Shen, Marina
%A Zhang, Wen
%A Gonzalez, Mario
%A Liu, Shanghao
%A Mahadevan, Anu
%A Sard, Howard
%A Khor, Soo Peang
%A Clark, James D.
%D 2006
%T Inhibition of Cytosolic Phospholipase A2α: Hit to Lead Optimization
%U https://acs.figshare.com/articles/journal_contribution/Inhibition_of_Cytosolic_Phospholipase_A_sub_2_sub_Hit_to_Lead_Optimization/3244027
%R 10.1021/jm0507882.s001
%2 https://acs.figshare.com/ndownloader/files/5078122
%K blood assays
%K IC 50
%K lipid
%K benzoic acid moieties
%K cPLA 2 α inhibition
%K GLU
%K micelle
%K cPLA 2 α
%K inhibitor
%X Compound 1 was previously reported to be a potent inhibitor of cPLA2α 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 IC50 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-γ-linolenate) micelle assay, which contains lipid and detergent. Extensive
structure−activity relationship work around this lead identified a potent pharmacophore for cPLA2α inhibition.
The IC50s 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 cPLA2α and represent well-validated starting points
for further optimization.
%I ACS Publications