2-Oxoamide inhibitors of cytosolic group IVA phospholipase A2 with reduced lipophilicity.

Cytosolic GIVA phospholipase A 2 (GIVA cPLA 2 ) initiates the eicosanoid pathway of inflammation and thus inhibitors of this enzyme constitute novel potential agents for the treatment of inflammatory diseases. Traditionally, GIVA cPLA 2 inhibitors have suffered systemically from high lipophilicity. We have developed a variety of long chain 2-oxoamides as inhibitors of GIVA PLA 2 . Among them, AX048 was found to produce a potent analgesic effect. We have now reduced the lipophilicity of AX048 by replacing the long aliphatic chain with a chain containing an ether linked aromatic ring with in vitro inhibitory activities similar to AX048. [ABSTRACT FROM AUTHOR]