Abstract
The Group IVA cytosolic phospholipase A2 (GIVA cPLA2) is a key provider of substrates for the production of eicosanoids and platelet-activating factor. We explored the structure-activity relationship of 2-oxoamide-based compounds and GIVA cPLA2 inhibition. The most potent inhibitors are derived from delta- and gamma-amino acid-based 2-oxoamides. The optimal side-chain moiety is a short nonpolar aliphatic chain. All of the newly developed 2-oxoamides as well as those previously described have now been tested with the human Group V secreted PLA2 (GV sPLA2) and the human Group VIA calcium-independent PLA2 (GVIA iPLA2). Only one 2-oxoamide compound had appreciable inhibition of GV sPLA2, and none of the potent GIVA cPLA2 inhibitors inhibited either GV sPLA2 or GVIA iPLA2. Two of these specific GIVA cPLA2 inhibitors were also found to have potent therapeutic effects in animal models of pain and inflammation at dosages well below the control nonsteroidal anti-inflammatory drugs.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Amides / pharmacology
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Amino Acids / chemical synthesis*
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Amino Acids / chemistry
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Amino Acids / pharmacology
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
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Anti-Inflammatory Agents, Non-Steroidal / chemistry
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Carrageenan
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Edema / chemically induced
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Edema / drug therapy
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Group IV Phospholipases A2
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Group V Phospholipases A2
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Group VI Phospholipases A2
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Humans
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Inflammation / drug therapy
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Pain / drug therapy
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Phospholipases A / antagonists & inhibitors*
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Phospholipases A2
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Rats
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Amides
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Amino Acids
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Anti-Inflammatory Agents, Non-Steroidal
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Carrageenan
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Phospholipases A
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Group IV Phospholipases A2
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Group V Phospholipases A2
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Group VI Phospholipases A2
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PLA2G4A protein, human
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PLA2G5 protein, human
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PLA2G6 protein, human
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Phospholipases A2
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Pla2g4a protein, rat
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Pla2g5 protein, rat