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.
Gopalsamy
Ariamala
A
Chemical and Screening Sciences, Wyeth Research, Pearl River, NY 10965, USA. gopalsa@wyeth.com
Yang
Hui
H
Ellingboe
John W
JW
McKew
John C
JC
Tam
Steve
S
Joseph-McCarthy
Diane
D
Zhang
Wen
W
Shen
Marina
M
Clark
James D
JD
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