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Open AccessArticle

2-Oxoester Phospholipase A2 Inhibitors with Enhanced Metabolic Stability

Department of Chemistry, National and Kapodistrian University of Athens, Athens 15771, Greece
Department of Chemistry and Biochemistry and Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0601, USA
Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(3), 491; (registering DOI)
Received: 1 March 2020 / Revised: 19 March 2020 / Accepted: 20 March 2020 / Published: 24 March 2020
(This article belongs to the Special Issue Phospholipases: From Structure to Biological Function)
2-Oxoesters constitute an important class of potent and selective inhibitors of human cytosolic phospholipase A2 (GIVA cPLA2) combining an aromatic scaffold or a long aliphatic chain with a short aliphatic chain containing a free carboxylic acid. Although highly potent 2-oxoester inhibitors of GIVA cPLA2 have been developed, their rapid degradation in human plasma limits their pharmaceutical utility. In an effort to address this problem, we designed and synthesized two new 2-oxoesters introducing a methyl group either on the α-carbon to the oxoester functionality or on the carbon carrying the ester oxygen. We studied the in vitro plasma stability of both derivatives and their in vitro inhibitory activity on GIVA cPLA2. Both derivatives exhibited higher plasma stability in comparison with the unsubstituted compound and both derivatives inhibited GIVA cPLA2, however to different degrees. The 2-oxoester containing a methyl group on the α-carbon atom to the oxoester functionality exhibits enhancement of the metabolic stability and retains considerable inhibitory potency. View Full-Text
Keywords: inhibitor; metabolic stability; α-methylation; oxoesters; phospholipase A2 inhibitor; metabolic stability; α-methylation; oxoesters; phospholipase A2
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Koutoulogenis, G.S.; Kokotou, M.G.; Hayashi, D.; Mouchlis, V.D.; Dennis, E.A.; Kokotos, G. 2-Oxoester Phospholipase A2 Inhibitors with Enhanced Metabolic Stability. Biomolecules 2020, 10, 491.

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