title: 2-Oxoamides based on dipeptides as selective calcium-independent phospholipase A2inhibitors.
abstract: Calcium-independent phospholipase A2(GVIA iPLA2) has recently attracted interest as a medicinal target. The number of known GVIA iPLA2inhibitors is limited to a handful of synthetic compounds (bromoenol lactone and polyfluoroketones). To expand the chemical diversity, a variety of 2-oxoamides based on dipeptides and ether dipeptides were synthesized and studied for their in vitro inhibitory activity on human GVIA iPLA2and their selectivity over the other major intracellular GIVA cPLA2and the secreted GV sPLA2. Structure-activity relationship studies revealed the first 2-oxoamide derivative (GK317), which presents potent inhibition of GVIA iPLA2(XI(50) value of 0.007) and at the same time significant selectivity over GIVA cPLA2and GV sPLA2.
authors.affiliation: Chemical Laboratories, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece.
authors.forename: Anneta
authors.initials: A
authors.lastname: Smyrniotou
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece; Department of Pharmacology and Department of Chemistry and Biochemistry, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0601, USA.
authors.forename: Maroula G
authors.initials: MG
authors.lastname: Kokotou
authors.affiliation: Department of Pharmacology and Department of Chemistry and Biochemistry, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0601, USA.
authors.forename: Varnavas D
authors.initials: VD
authors.lastname: Mouchlis
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors.forename: Efrosini
authors.initials: E
authors.lastname: Barbayianni
authors.affiliation: Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kokotos
authors.affiliation: Department of Pharmacology and Department of Chemistry and Biochemistry, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0601, USA. Electronic address: edennis@ucsd.edu.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Dennis
authors.affiliation: Chemical Laboratories, Agricultural University of Athens, Iera Odos 75, Athens 11855, Greece. Electronic address: vikon@aua.gr.
authors.forename: Violetta
authors.initials: V
authors.lastname: Constantinou-Kokotou
mesh_terms: D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D064801:Phospholipase A2 Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054512:Phospholipases A2, Calcium-Independent / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004151:Dipeptides; D064801:Phospholipase A2 Inhibitors; D011725:Pyridines; C034960:oxoamide; D054512:Phospholipases A2, Calcium-Independent
keywords: Dipeptides; Inhibitors; Oxoamides; Phospholipase A(2); Pseudodipeptides