Discovery of Ecopladib, an indole inhibitor of cytosolic phospholipase A2alpha.
The synthesis and structure-activity relationship of a series of indole inhibitors of cytosolic phospholipase A2alpha (cPLA2alpha, type IVA phospholipase) are described. Inhibitors of cPLA2alpha are predicted to be efficacious in treating asthma as well as the signs and symptoms of osteoarthritis, rheumatoid arthritis, and pain. The introduction of a benzyl sulfonamide substituent at C2 was found to impart improved potency of these inhibitors, and the SAR of these sulfonamide analogues is disclosed. Compound 123 (Ecopladib) is a sub-micromolar inhibitor of cPLA2alpha in the GLU micelle and rat whole blood assays. Compound 123 displayed oral efficacy in the rat carrageenan air pouch and rat carrageenan-induced paw edema models.
Lee
Katherine L
KL
Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA. klee@wyeth.com
Foley
Megan A
MA
Chen
Lihren
L
Behnke
Mark L
ML
Lovering
Frank E
FE
Kirincich
Steven J
SJ
Wang
Weiheng
W
Shim
Jaechul
J
Tam
Steve
S
Shen
Marina W H
MW
Khor
Soopeang
S
Xu
Xin
X
Goodwin
Debra G
DG
Ramarao
Manjunath K
MK
Nickerson-Nutter
Cheryl
C
Donahue
Frances
F
Ku
M Sherry
MS
Clark
James D
JD
McKew
John C
JC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001565:Benzoates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002351:Carrageenan; D003600:Cytosol / Q000201:enzymology*; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D054513:Group IV Phospholipases A2; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D007211:Indoles; D013449:Sulfonamides; C519110:ecopladib; D002351:Carrageenan; D010741:Phospholipases A; D054513:Group IV Phospholipases A2