Literature DB >> 27522578

2-Oxoamide inhibitors of cytosolic group IVA phospholipase A2 with reduced lipophilicity.

Georgia Antonopoulou1, Victoria Magrioti2, Maroula G Kokotou2, Aikaterini Nikolaou2, Efrosini Barbayianni2, Varnavas D Mouchlis3, Edward A Dennis4, George Kokotos5.   

Abstract

Cytosolic GIVA phospholipase A2 (GIVA cPLA2) initiates the eicosanoid pathway of inflammation and thus inhibitors of this enzyme constitute novel potential agents for the treatment of inflammatory diseases. Traditionally, GIVA cPLA2 inhibitors have suffered systemically from high lipophilicity. We have developed a variety of long chain 2-oxoamides as inhibitors of GIVA PLA2. Among them, AX048 was found to produce a potent analgesic effect. We have now reduced the lipophilicity of AX048 by replacing the long aliphatic chain with a chain containing an ether linked aromatic ring with in vitro inhibitory activities similar to AX048.
Copyright © 2016 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  2-Oxoamides; GIVA cPLA(2); Inhibitors; Lipophilicity; Phospholipase A(2)

Mesh：

Substances：

Year:  2016        PMID： 27522578      PMCID： PMC5014611          DOI： 10.1016/j.bmc.2016.07.057

Source DB:  PubMed          Journal:  Bioorg Med Chem        ISSN： 0968-0896            Impact factor:   3.641


  34 in total

1.  Synthesis and evaluation of substrate-mimicking cytosolic phospholipase A2 inhibitors--reducing the lipophilicity of the arachidonyl chain isostere.

Authors:  Iain Walters; Colin Bennion; Stephen Connolly; Pamela J Croshaw; Kim Hardy; Paul Hartopp; Clive G Jackson; Sarah J King; Louise Lawrence; Antonio Mete; David Murray; David H Robinson; Linda Stein; Edward Wells; W John Withnall
Journal:  Bioorg Med Chem Lett       Date:  2004-07-16       Impact factor: 2.823

2.  Structure-activity relationship of 2-oxoamide inhibition of group IVA cytosolic phospholipase A2 and group V secreted phospholipase A2.

Authors:  David A Six; Efrosini Barbayianni; Vassilios Loukas; Violetta Constantinou-Kokotou; Dimitra Hadjipavlou-Litina; Daren Stephens; Alan C Wong; Victoria Magrioti; Panagiota Moutevelis-Minakakis; Sharon F Baker; Edward A Dennis; George Kokotos
Journal:  J Med Chem       Date:  2007-08-02       Impact factor: 7.446

3.  Design and synthesis of 1-indol-1-yl-propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha.

Authors:  Joachim Ludwig; Stefanie Bovens; Carsten Brauch; Alwine Schulze Elfringhoff; Matthias Lehr
Journal:  J Med Chem       Date:  2006-04-20       Impact factor: 7.446

4.  Discovery of Ecopladib, an indole inhibitor of cytosolic phospholipase A2alpha.

Authors:  Katherine L Lee; Megan A Foley; Lihren Chen; Mark L Behnke; Frank E Lovering; Steven J Kirincich; Weiheng Wang; Jaechul Shim; Steve Tam; Marina W H Shen; Soopeang Khor; Xin Xu; Debra G Goodwin; Manjunath K Ramarao; Cheryl Nickerson-Nutter; Frances Donahue; M Sherry Ku; James D Clark; John C McKew
Journal:  J Med Chem       Date:  2007-02-17       Impact factor: 7.446

5.  1-Indol-1-yl-propan-2-ones and related heterocyclic compounds as dual inhibitors of cytosolic phospholipase A(2)alpha and fatty acid amide hydrolase.

Authors:  Laura Forster; Joachim Ludwig; Martina Kaptur; Stefanie Bovens; Alwine Schulze Elfringhoff; Angela Holtfrerich; Matthias Lehr
Journal:  Bioorg Med Chem       Date:  2009-11-17       Impact factor: 3.641

6.  Design and synthesis of a novel and potent series of inhibitors of cytosolic phospholipase A(2) based on a 1,3-disubstituted propan-2-one skeleton.

Authors:  Stephen Connolly; Colin Bennion; Sarah Botterell; Pamela J Croshaw; Catherine Hallam; Kim Hardy; Paul Hartopp; Clive G Jackson; Sarah J King; Louise Lawrence; Antonio Mete; David Murray; David H Robinson; Gillian M Smith; Linda Stein; Iain Walters; Edward Wells; W John Withnall
Journal:  J Med Chem       Date:  2002-03-14       Impact factor: 7.446

7.  1-(5-Carboxy- and 5-carbamoylindol-1-yl)propan-2-ones as inhibitors of human cytosolic phospholipase A2alpha: bioisosteric replacement of the carboxylic acid and carboxamide moiety.

Authors:  Mark Hess; Alwine Schulze Elfringhoff; Matthias Lehr
Journal:  Bioorg Med Chem       Date:  2007-02-13       Impact factor: 3.641

8.  Reactions of functionalized sulfonamides: application to lowering the lipophilicity of cytosolic phospholipase A2alpha inhibitors.

Authors:  Lihren Chen; Weiheng Wang; Katherine L Lee; Marina W H Shen; Elizabeth A Murphy; Wen Zhang; Xin Xu; Steve Tam; Cheryl Nickerson-Nutter; Debra G Goodwin; James D Clark; John C McKew
Journal:  J Med Chem       Date:  2009-02-26       Impact factor: 7.446

9.  Slow- and tight-binding inhibitors of the 85-kDa human phospholipase A2.

Authors:  I P Street; H K Lin; F Laliberté; F Ghomashchi; Z Wang; H Perrier; N M Tremblay; Z Huang; P K Weech; M H Gelb
Journal:  Biochemistry       Date:  1993-06-15       Impact factor: 3.162

10.  Novel 2-oxoamide inhibitors of human group IVA phospholipase A(2).

Authors:  George Kokotos; Stavroula Kotsovolou; David A Six; Violetta Constantinou-Kokotou; Christopher C Beltzner; Edward A Dennis
Journal:  J Med Chem       Date:  2002-07-04       Impact factor: 7.446
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  2 in total

Review 1.  Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2.

Authors:  Aikaterini Nikolaou; Maroula G Kokotou; Sofia Vasilakaki; George Kokotos
Journal:  Biochim Biophys Acta Mol Cell Biol Lipids       Date:  2018-08-23       Impact factor: 4.698

2.  2-Oxoesters: A Novel Class of Potent and Selective Inhibitors of Cytosolic Group IVA Phospholipase A2.

Authors:  Maroula G Kokotou; Gerasimia Galiatsatou; Victoria Magrioti; Giorgos Koutoulogenis; Efrosini Barbayianni; Dimitris Limnios; Varnavas D Mouchlis; Banita Satpathy; Aaron Navratil; Edward A Dennis; George Kokotos
Journal:  Sci Rep       Date:  2017-08-01       Impact factor: 4.379
  2 in total

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