Inhibition of group IVA cytosolic phospholipase A2 by novel 2-oxoamides in vitro, in cells, and in vivo

J Med Chem. 2004 Jul 1;47(14):3615-28. doi: 10.1021/jm030485c.

Abstract

The Group IVA cytosolic phospholipase A(2) (GIVA PLA(2)) is a particularly attractive target for drug development because it is the rate-limiting provider of proinflammatory mediators. We previously reported the discovery of novel 2-oxoamides that inhibit GIVA PLA(2) [Kokotos, G.; et al. J. Med. Chem. 2002, 45, 2891-2893]. In the present work, we have further explored this class of inhibitors and found that the 2-oxoamide functionality is more potent when it contains a long 2-oxoacyl residue and a free carboxy group. Long-chain 2-oxoamides based on gamma-aminobutyric acid and gamma-norleucine are potent inhibitors of GIVA PLA(2). Such inhibitors act through a fast and reversible mode of inhibition in vitro, are able to block the production of arachidonic acid and prostaglandin E(2) in cells, and demonstrate potent in vivo anti-inflammatory and analgesic activity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Aminobutyrates
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Butyrates / chemical synthesis*
  • Butyrates / chemistry
  • Butyrates / pharmacology
  • Caprylates / chemical synthesis*
  • Caprylates / chemistry
  • Caprylates / pharmacology
  • Cell Line
  • Edema / drug therapy
  • Group IV Phospholipases A2
  • Heptanoic Acids / chemical synthesis*
  • Heptanoic Acids / chemistry
  • Heptanoic Acids / pharmacology
  • Macrophage Activation
  • Mice
  • Pain Measurement
  • Phospholipases A / antagonists & inhibitors*
  • Phospholipases A / chemistry
  • Phospholipases A2
  • Rats
  • Rats, Inbred F344
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 4-((2-oxododecanoyl)amino)octanoic acid
  • 4-((2-oxohexadecanoyl)amino)butanoic acid
  • 6-methyl-4-((2-oxopentadecanoyl)amino)heptanoic acid
  • Amides
  • Aminobutyrates
  • Anti-Inflammatory Agents, Non-Steroidal
  • Butyrates
  • Caprylates
  • Heptanoic Acids
  • Pla2g4a protein, mouse
  • Phospholipases A
  • Group IV Phospholipases A2
  • Phospholipases A2
  • Pla2g4a protein, rat