Inhibition of cytosolic phospholipase A2alpha: hit to lead optimization.
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.
McKew
John C
JC
Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA. jmckew@wyeth.com
Foley
Megan A
MA
Thakker
Paresh
P
Behnke
Mark L
ML
Lovering
Frank E
FE
Sum
Fuk-Wah
FW
Tam
Steve
S
Wu
Kun
K
Shen
Marina W H
MW
Zhang
Wen
W
Gonzalez
Mario
M
Liu
Shanghao
S
Mahadevan
Anu
A
Sard
Howard
H
Khor
Soo Peang
SP
Clark
James D
JD
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003600:Cytosol / Q000201:enzymology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D054513:Group IV Phospholipases A2; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007211:Indoles; D010741:Phospholipases A; D054513:Group IV Phospholipases A2