Differential inhibition of group IVA and group VIA phospholipases A2 by 2-oxoamides.
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.
Stephens
Daren
D
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0601, USA.
Barbayianni
Efrosini
E
Constantinou-Kokotou
Violetta
V
Peristeraki
Anna
A
Six
David A
DA
Cooper
Jennifer
J
Harkewicz
Richard
R
Deems
Raymond A
RA
Dennis
Edward A
EA
Kokotos
George
G
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
D004791:Enzyme Inhibitors; D011725:Pyridines; C034960:oxoamide; D010741:Phospholipases A; D015232:Dinoprostone