title: Indole cytosolic phospholipase A2 alpha inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)-1H-indol-3-yl]propyl}benzoic acid, efipladib.
abstract: The optimization of a class of indole cPLA 2 alpha inhibitors is described herein. The importance of the substituent at C3 and the substitution pattern of the phenylmethane sulfonamide region are highlighted. Optimization of these regions led to the discovery of 111 (efipladib) and 121 (WAY-196025), which are shown to be potent, selective inhibitors of cPLA 2 alpha in a variety of isolated enzyme assays, cell based assays, and rat and human whole blood assays. The binding of these compounds has been further examined using isothermal titration calorimetry. Finally, these compounds have shown efficacy when dosed orally in multiple acute and chronic prostaglandin and leukotriene dependent in vivo models.
authors.affiliation: Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. jmckew@wyeth.com
authors.forename: John C
authors.initials: JC
authors.lastname: McKew
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Lee
authors.forename: Marina W H
authors.initials: MW
authors.lastname: Shen
authors.forename: Paresh
authors.initials: P
authors.lastname: Thakker
authors.forename: Megan A
authors.initials: MA
authors.lastname: Foley
authors.forename: Mark L
authors.initials: ML
authors.lastname: Behnke
authors.forename: Baihua
authors.initials: B
authors.lastname: Hu
authors.forename: Fuk-Wah
authors.initials: FW
authors.lastname: Sum
authors.forename: Steve
authors.initials: S
authors.lastname: Tam
authors.forename: Yonghan
authors.initials: Y
authors.lastname: Hu
authors.forename: Lihren
authors.initials: L
authors.lastname: Chen
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Kirincich
authors.forename: Ronald
authors.initials: R
authors.lastname: Michalak
authors.forename: Jennifer
authors.initials: J
authors.lastname: Thomason
authors.forename: Manus
authors.initials: M
authors.lastname: Ipek
authors.forename: Kun
authors.initials: K
authors.lastname: Wu
authors.forename: Lane
authors.initials: L
authors.lastname: Wooder
authors.forename: Manjunath K
authors.initials: MK
authors.lastname: Ramarao
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Murphy
authors.forename: Debra G
authors.initials: DG
authors.lastname: Goodwin
authors.forename: Leo
authors.initials: L
authors.lastname: Albert
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Frances
authors.initials: F
authors.lastname: Donahue
authors.forename: M Sherry
authors.initials: MS
authors.lastname: Ku
authors.forename: James
authors.initials: J
authors.lastname: Keith
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Nickerson-Nutter
authors.forename: William M
authors.initials: WM
authors.lastname: Abraham
authors.forename: Cara
authors.initials: C
authors.lastname: Williams
authors.forename: Martin
authors.initials: M
authors.lastname: Hegen
authors.forename: James D
authors.initials: JD
authors.lastname: Clark
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D016084:Bronchoconstriction / Q000187:drug effects; D002151:Calorimetry; D002351:Carrageenan; D002460:Cell Line; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D012756:Sheep; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C531069:4-(3-(5-chloro-2-(2-(((2,6-dimethylbenzyl)sulfonyl)amino)ethyl)-1-(diphenylmethyl)-1H-indol-3-yl)propyl)benzoic acid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001565:Benzoates; D052246:Cyclooxygenase 2 Inhibitors; D007527:Isoenzymes; D013449:Sulfonamides; D002351:Carrageenan; D054513:Group IV Phospholipases A2; C531068:efipladib