Structure-activity relationships of indole cytosolic phospholipase A(2)alpha inhibitors: substrate mimetics.
An SAR effort focused on generating cPLA(2)alpha inhibitors using a substrate mimetic approach is reported. Indole inhibitors of cPLA(2)alpha with promising pharmacokinetic parameters that were active in both an isolated enzyme assay and in cell-based assays were discovered. Modeling these compounds into the cPLA(2)alpha structure validated the assumptions made at the start of the SAR effort.
McKew
John C
JC
Departments of Chemical and Screening Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge, MA 02140, USA. jmckew@wyeth.com
Lovering
Frank
F
Clark
James D
JD
Bemis
Jean
J
Xiang
YiBin
Y
Shen
Marina
M
Zhang
Wen
W
Alvarez
Juan C
JC
Joseph-McCarthy
Diane
D
D001665:Binding Sites; D054513:Group IV Phospholipases A2; D007202:Indicators and Reagents; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D008968:Molecular Conformation; D010741:Phospholipases A / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation; D055672:Static Electricity; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D007211:Indoles; D010741:Phospholipases A; D054513:Group IV Phospholipases A2