Indole cytosolic phospholipase A2 α 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

John C. McKew, Katherine L. Lee, Marina W H Shen, Paresh Thakker, Megan A. Foley, Mark L. Behnke, Baihua Hu, Fuk Wah Sum, Steve Tam, Yonghan Hu, Lihren Chen, Steven J. Kirincich, Ronald Michalak, Jennifer Thomason, Manus Ipek, Kun Wu, Lane Wooder, Manjunath K. Ramarao, Elizabeth A. Murphy, Debra G. Goodwin & 10 others Leo Albert, Xin Xu, Frances Donahue, M. Sherry Ku, James Keith, Cheryl L. Nickerson-Nutter, William M. Abraham, Cara Williams, Martin Hegen, James D. Clark

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

The optimization of a class of indole cPLA2α 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 cPLA2α 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.

Original languageEnglish
Pages (from-to)3388-3413
Number of pages26
JournalJournal of Medicinal Chemistry
Volume51
Issue number12
DOIs
StatePublished - Jun 26 2008
Externally publishedYes

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Phospholipase A2 Inhibitors
Calorimetry
Leukotrienes
Sulfonamides
Enzyme Assays
Prostaglandins
Assays
Titration
Rats
Blood
Substitution reactions
Enzymes
efipladib
indole
4-(3-(5-chloro-2-(2-(((2,6-dimethylbenzyl)sulfonyl)amino)ethyl)-1-(diphenylmethyl)-1H-indol-3-yl)propyl)benzoic acid
In Vitro Techniques

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Indole cytosolic phospholipase A2 α 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. / McKew, John C.; Lee, Katherine L.; Shen, Marina W H; Thakker, Paresh; Foley, Megan A.; Behnke, Mark L.; Hu, Baihua; Sum, Fuk Wah; Tam, Steve; Hu, Yonghan; Chen, Lihren; Kirincich, Steven J.; Michalak, Ronald; Thomason, Jennifer; Ipek, Manus; Wu, Kun; Wooder, Lane; Ramarao, Manjunath K.; Murphy, Elizabeth A.; Goodwin, Debra G.; Albert, Leo; Xu, Xin; Donahue, Frances; Ku, M. Sherry; Keith, James; Nickerson-Nutter, Cheryl L.; Abraham, William M.; Williams, Cara; Hegen, Martin; Clark, James D.

In: Journal of Medicinal Chemistry, Vol. 51, No. 12, 26.06.2008, p. 3388-3413.

Research output: Contribution to journalArticle

McKew, JC, Lee, KL, Shen, MWH, Thakker, P, Foley, MA, Behnke, ML, Hu, B, Sum, FW, Tam, S, Hu, Y, Chen, L, Kirincich, SJ, Michalak, R, Thomason, J, Ipek, M, Wu, K, Wooder, L, Ramarao, MK, Murphy, EA, Goodwin, DG, Albert, L, Xu, X, Donahue, F, Ku, MS, Keith, J, Nickerson-Nutter, CL, Abraham, WM, Williams, C, Hegen, M & Clark, JD 2008, 'Indole cytosolic phospholipase A2 α 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', Journal of Medicinal Chemistry, vol. 51, no. 12, pp. 3388-3413. https://doi.org/10.1021/jm701467e
McKew, John C. ; Lee, Katherine L. ; Shen, Marina W H ; Thakker, Paresh ; Foley, Megan A. ; Behnke, Mark L. ; Hu, Baihua ; Sum, Fuk Wah ; Tam, Steve ; Hu, Yonghan ; Chen, Lihren ; Kirincich, Steven J. ; Michalak, Ronald ; Thomason, Jennifer ; Ipek, Manus ; Wu, Kun ; Wooder, Lane ; Ramarao, Manjunath K. ; Murphy, Elizabeth A. ; Goodwin, Debra G. ; Albert, Leo ; Xu, Xin ; Donahue, Frances ; Ku, M. Sherry ; Keith, James ; Nickerson-Nutter, Cheryl L. ; Abraham, William M. ; Williams, Cara ; Hegen, Martin ; Clark, James D. / Indole cytosolic phospholipase A2 α 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. In: Journal of Medicinal Chemistry. 2008 ; Vol. 51, No. 12. pp. 3388-3413.
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AU - McKew, John C.

AU - Lee, Katherine L.

AU - Shen, Marina W H

AU - Thakker, Paresh

AU - Foley, Megan A.

AU - Behnke, Mark L.

AU - Hu, Baihua

AU - Sum, Fuk Wah

AU - Tam, Steve

AU - Hu, Yonghan

AU - Chen, Lihren

AU - Kirincich, Steven J.

AU - Michalak, Ronald

AU - Thomason, Jennifer

AU - Ipek, Manus

AU - Wu, Kun

AU - Wooder, Lane

AU - Ramarao, Manjunath K.

AU - Murphy, Elizabeth A.

AU - Goodwin, Debra G.

AU - Albert, Leo

AU - Xu, Xin

AU - Donahue, Frances

AU - Ku, M. Sherry

AU - Keith, James

AU - Nickerson-Nutter, Cheryl L.

AU - Abraham, William M.

AU - Williams, Cara

AU - Hegen, Martin

AU - Clark, James D.

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