1,2,4-Oxadiazolidin-3,5-diones and 1,3,5-triazin-2,4,6-triones as cytosolic phospholipase A2alpha inhibitors.
1,2,4-Oxadiazolidin-3,5-dione and 1,3,5-triazin-2,4,6-trione scaffolds were employed as templates to incorporate the pharmacophore requirements of cytosolic phospholipase A2alpha substrate mimetics. Inhibitors that are active in both enzyme, and cell-based assays were identified from both classes. From the SAR work carried out and modeling efforts around these templates, the triazinetrione scaffold with an additional substitution point was found to be more favorable.
Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA. gopalsa@wyeth.com
Ariamala
A
Gopalsamy
Hui
H
Yang
John W
JW
Ellingboe
John C
JC
McKew
Steve
S
Tam
Diane
D
Joseph-McCarthy
Wen
W
Zhang
Marina
M
Shen
James D
JD
Clark
D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054513:Group IV Phospholipases A2; D008958:Models, Molecular; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D014227:Triazines; D010741:Phospholipases A; D054513:Group IV Phospholipases A2