Design and synthesis of a novel and potent series of inhibitors of cytosolic phospholipase A(2) based on a 1,3-disubstituted propan-2-one skeleton.
Using knowledge of the substrate specificity of cPLA(2) (phospholipases A(2)), a novel series of inhibitors of this enzyme were designed based upon a three point model of inhibitor binding to the enzyme active site comprising a lipophilic anchor, an electrophilic serine "trap", and an acidic binding moiety. The resulting 1,3-diheteroatom-substituted propan-2-ones were evaluated as inhibitors of cPLA(2) in both aggregated bilayer and soluble substrate assays. Systematic variation of the lipophilic, electrophilic, and acidic groups revealed a well-defined structure-activity relationship against the enzyme. Optimization of each group led to compound 22 (AR-C70484XX), which contains a decyloxy lipophilic side chain, a 1,3-diaryloxypropan-2-one moiety as a unique serine trap, and a benzoic acid as the acidic binding group. AR-C70484XX was found to be among the most potent in vitro inhibitors of cPLA(2) described to date being more than 20-fold more active against the isolated enzyme (IC(50) = 0.03 microM) than the standard cPLA(2) inhibitor, arachidonyl trifluoromethyl ketone (AACOCF(3)), and also greater than 10-fold more active than AACOCF(3) against the cellular production of arachidonic acid by HL60 cells (IC(50) = 2.8 microM).
Connolly
Stephen
S
Department of Medicinal Chemistry, AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, United Kingdom. steve.connolly@astrazeneca.com
Bennion
Colin
C
Botterell
Sarah
S
Croshaw
Pamela J
PJ
Hallam
Catherine
C
Hardy
Kim
K
Hartopp
Paul
P
Jackson
Clive G
CG
King
Sarah J
SJ
Lawrence
Louise
L
Mete
Antonio
A
Murray
David
D
Robinson
David H
DH
Smith
Gillian M
GM
Stein
Linda
L
Walters
Iain
I
Wells
Edward
E
Withnall
W John
WJ
D016718:Arachidonic Acid / Q000032:analysis / Q000096:biosynthesis; D003600:Cytosol / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007659:Ketones / Q000138:chemical synthesis / Q000494:pharmacology; D008051:Lipid Bilayers / Q000378:metabolism; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D011407:Propane / Q000031:analogs & derivatives*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D007659:Ketones; D008051:Lipid Bilayers; D016718:Arachidonic Acid; D010741:Phospholipases A; D011407:Propane