title: Discovery of Ecopladib, an indole inhibitor of cytosolic phospholipase A2alpha.
abstract: 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.
authors.affiliation: Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 02140, USA. klee@wyeth.com
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Lee
authors.forename: Megan A
authors.initials: MA
authors.lastname: Foley
authors.forename: Lihren
authors.initials: L
authors.lastname: Chen
authors.forename: Mark L
authors.initials: ML
authors.lastname: Behnke
authors.forename: Frank E
authors.initials: FE
authors.lastname: Lovering
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kirincich
authors.forename: Weiheng
authors.initials: W
authors.lastname: Wang
authors.forename: Jaechul
authors.initials: J
authors.lastname: Shim
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: Marina W H
authors.initials: MW
authors.lastname: Shen
authors.forename: Soopeang
authors.initials: S
authors.lastname: Khor
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Debra G
authors.initials: DG
authors.lastname: Goodwin
authors.forename: Manjunath K
authors.initials: MK
authors.lastname: Ramarao
authors.forename: Cheryl
authors.initials: C
authors.lastname: Nickerson-Nutter
authors.forename: Frances
authors.initials: F
authors.lastname: Donahue
authors.forename: M Sherry
authors.initials: MS
authors.lastname: Ku
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
mesh_terms: 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
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D007211:Indoles; D013449:Sulfonamides; C519110:ecopladib; D002351:Carrageenan; D010741:Phospholipases A; D054513:Group IV Phospholipases A2