title: 2-Oxoamide inhibitors of cytosolic group IVA phospholipase A2 with reduced lipophilicity.
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.
authors: 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.
authors: Georgia
authors: G
authors: Antonopoulou
authors: Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors: Victoria
authors: V
authors: Magrioti
authors: Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors: Maroula G
authors: MG
authors: Kokotou
authors: Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors: Aikaterini
authors: A
authors: Nikolaou
authors: Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors: Efrosini
authors: E
authors: Barbayianni
authors: 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.
authors: Varnavas D
authors: VD
authors: Mouchlis
authors: 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.
authors: Edward A
authors: EA
authors: Dennis
authors: Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece. Electronic address: gkokotos@chem.uoa.gr.
authors: George
authors: G
authors: Kokotos
mesh_terms: D000818:Animals; D003600:Cytosol / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; C034960:oxoamide; D054513:Group IV Phospholipases A2
keywords: 2-Oxoamides; GIVA cPLA(2); Inhibitors; Lipophilicity; Phospholipase A(2)