2-Oxoamides based on dipeptides as selective calcium-independent phospholipase A2 inhibitors

[Display omitted] Calcium-independent phospholipase A2 (GVIA iPLA2) has recently attracted interest as a medicinal target. The number of known GVIA iPLA2 inhibitors is limited to a handful of synthetic compounds (bromoenol lactone and polyfluoroketones). To expand the chemical diversity, a variety o...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2017-02, Vol.25 (3), p.926-940
Main Authors: Smyrniotou, Anneta, Kokotou, Maroula G., Mouchlis, Varnavas D., Barbayianni, Efrosini, Kokotos, George, Dennis, Edward A., Constantinou-Kokotou, Violetta
Format: Article
Language:English
Subjects:
Dipeptides
Inhibitors
Oxoamides
Phospholipase A2
Pseudodipeptides
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Summary:[Display omitted] Calcium-independent phospholipase A2 (GVIA iPLA2) has recently attracted interest as a medicinal target. The number of known GVIA iPLA2 inhibitors 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 iPLA2 and their selectivity over the other major intracellular GIVA cPLA2 and 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 cPLA2 and GV sPLA2.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2016.12.007