title: Inhibition of group IVA cytosolic phospholipase A2 by novel 2-oxoamides in vitro, in cells, and in vivo.
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.
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, University of Athens, Panepistimiopolis, Athens 15771, Greece. gkokotos@cc.uoa.gr
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
authors.forename: David A
authors.initials: DA
authors.lastname: Six
authors.forename: Vassilios
authors.initials: V
authors.lastname: Loukas
authors.forename: Timothy
authors.initials: T
authors.lastname: Smith
authors.forename: Violetta
authors.initials: V
authors.lastname: Constantinou-Kokotou
authors.forename: Dimitra
authors.initials: D
authors.lastname: Hadjipavlou-Litina
authors.forename: Stavroula
authors.initials: S
authors.lastname: Kotsovolou
authors.forename: Antonia
authors.initials: A
authors.lastname: Chiou
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Beltzner
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000613:Aminobutyrates; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002087:Butyrates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002210:Caprylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004487:Edema / Q000188:drug therapy; D054513:Group IV Phospholipases A2; D006538:Heptanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008262:Macrophage Activation; D051379:Mice; D010147:Pain Measurement; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054467:Phospholipases A2; D051381:Rats; D011916:Rats, Inbred F344; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C488114:4-((2-oxododecanoyl)amino)octanoic acid; C488113:4-((2-oxohexadecanoyl)amino)butanoic acid; C488115:6-methyl-4-((2-oxopentadecanoyl)amino)heptanoic acid; D000577:Amides; D000613:Aminobutyrates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002087:Butyrates; D002210:Caprylates; D006538:Heptanoic Acids; C516390:Pla2g4a protein, mouse; D010741:Phospholipases A; D054513:Group IV Phospholipases A2; D054467:Phospholipases A2; C516391:Pla2g4a protein, rat