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.
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.
McKew
John C
JC
Department of Chemical and Screening Sciences, Wyeth Research, 200 CambridgePark Drive, Cambridge, MA 02140, USA. jmckew@wyeth.com
Lee
Katherine L
KL
Shen
Marina W H
MW
Thakker
Paresh
P
Foley
Megan A
MA
Behnke
Mark L
ML
Hu
Baihua
B
Sum
Fuk-Wah
FW
Tam
Steve
S
Hu
Yonghan
Y
Chen
Lihren
L
Kirincich
Steven J
SJ
Michalak
Ronald
R
Thomason
Jennifer
J
Ipek
Manus
M
Wu
Kun
K
Wooder
Lane
L
Ramarao
Manjunath K
MK
Murphy
Elizabeth A
EA
Goodwin
Debra G
DG
Albert
Leo
L
Xu
Xin
X
Donahue
Frances
F
Ku
M Sherry
MS
Keith
James
J
Nickerson-Nutter
Cheryl L
CL
Abraham
William M
WM
Williams
Cara
C
Hegen
Martin
M
Clark
James D
JD
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
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