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

Georgia Antonopoulou; Victoria Magrioti; Maroula G Kokotou; Aikaterini Nikolaou; Efrosini Barbayianni; Varnavas D Mouchlis; Edward A Dennis; George Kokotos

doi:10.1016/j.bmc.2016.07.057

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

Bioorg Med Chem. 2016 Oct 1;24(19):4544-4554. doi: 10.1016/j.bmc.2016.07.057. Epub 2016 Jul 27.

Authors

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

Affiliations

¹ Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece; Institute of Biology, Medicinal Chemistry and Biotechnology, National Hellenic Research Foundation, Athens, Greece.
² Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
³ Department of Chemistry and Biochemistry, School of Medicine, MC 0601, University of California, San Diego, La Jolla, CA 92093-0601, USA; Department of Pharmacology, School of Medicine, MC 0601, University of California, San Diego, La Jolla, CA 92093-0601, USA.
⁴ Department of Chemistry and Biochemistry, School of Medicine, MC 0601, University of California, San Diego, La Jolla, CA 92093-0601, USA; Department of Pharmacology, School of Medicine, MC 0601, University of California, San Diego, La Jolla, CA 92093-0601, USA. Electronic address: edennis@ucsd.edu.
⁵ Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece. Electronic address: gkokotos@chem.uoa.gr.

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.

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

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Cytosol / enzymology
Drug Design
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Group IV Phospholipases A2 / antagonists & inhibitors*
Group IV Phospholipases A2 / metabolism
Humans
Pyridines / chemistry*
Pyridines / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Pyridines
oxoamide
Group IV Phospholipases A2

Grants and funding

R01 GM020501/GM/NIGMS NIH HHS/United States