title: Differential inhibition of group IVA and group VIA phospholipases A2 by 2-oxoamides.
abstract: Inhibitors of the Group IVA phospholipase A(2) (GIVA cPLA(2)) and GVIA iPLA(2) are useful tools for defining the roles of these enzymes in cellular signaling and inflammation. We have developed inhibitors of GVIA iPLA(2) building upon the 2-oxoamide backbone that are uncharged, containing ester groups. Although the most potent inhibitors of GVIA iPLA(2) also inhibited GIVA cPLA(2), there were three 2-oxoamide compounds that selectively and weakly inhibited GVIA iPLA(2). We further show that several potent 2-oxoamide inhibitors of GIVA cPLA(2) containing free carboxylic groups (Kokotos et al. J. Med. Chem. 2002, 45, 2891-2893) do not inhibit GVIA iPLA(2) and are, therefore, selective GIVA cPLA(2) inhibitors.
authors.affiliation: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0601, USA.
authors.forename: Daren
authors.initials: D
authors.lastname: Stephens
authors.forename: Efrosini
authors.initials: E
authors.lastname: Barbayianni
authors.forename: Violetta
authors.initials: V
authors.lastname: Constantinou-Kokotou
authors.forename: Anna
authors.initials: A
authors.lastname: Peristeraki
authors.forename: David A
authors.initials: DA
authors.lastname: Six
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cooper
authors.forename: Richard
authors.initials: R
authors.lastname: Harkewicz
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Deems
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
mesh_terms: D000818:Animals; D002460:Cell Line; D015232:Dinoprostone / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000145:classification / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; C034960:oxoamide; D010741:Phospholipases A; D015232:Dinoprostone