Structure−Activity Relationship of 2-Oxoamide Inhibition of Group IVA Cytosolic Phospholipase A₂and Group V Secreted Phospholipase A₂

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.

Cytosolic phospholipase A2 alpha inhibitor, pyrroxyphene, displays anti-arthritic and anti-bone destructive action in a murine arthritis model

“…A previous study on cPLA2 alpha-deficient mice [10] led to the development of certain compounds and their examination in pharmacological studies [31][32][33][34]. However, it remained unclear whether the phenotype of cPLA2 alpha-deficient mice should be attributed to the reduction in eicosanoid production such as LTB 4 or PGE 2 [10].…”

Phospholipase A2 structure/function, mechanism, and signaling

“…Two of the most promising drug candidates include the indole derivative inhibitors developed by Wyeth, and the 2-oxoamide inhibitors developed by Six et al (39) and McKew et al (40). Both of these inhibitors have been used for in vivo animal models of inflammation and have shown potency in reducing inflammatory effects (40,41).…”

Macrophages: An elusive yet emerging therapeutic target of atherosclerosis

“…A recent article talks about compounds inhibiting different types of PLA2. 346 There are ample evidences, which demonstrate the generation and amplification of inflammatory responses by various lipids. Prior treatment of mouse macrophages with Ox-LDL lead to enhanced inflammatory response in response to LPS and this was postulated to be IL-10-dependent.…”