2-Oxoester Phospholipase A 2 Inhibitors with Enhanced Metabolic Stability

2-Oxoester Phospholipase A 2 Inhibitors with Enhanced Metabolic Stability

2-Oxoesters constitute an important class of potent and selective inhibitors of human cytosolic phospholipase A (GIVA cPLA ) 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 c...

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Veröffentlicht in:Biomolecules (Basel, Switzerland) Switzerland), 2020-03, Vol.10 (3)
Hauptverfasser: Koutoulogenis, Giorgos S, Kokotou, Maroula G, Hayashi, Daiki, Mouchlis, Varnavas D, Dennis, Edward A, Kokotos, George
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Sprache:eng
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Enzyme Stability
Esters - chemistry
Humans
Phospholipase A2 Inhibitors - chemistry
Phospholipases A2, Cytosolic - antagonists & inhibitors
Phospholipases A2, Cytosolic - chemistry
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container_title Biomolecules (Basel, Switzerland)
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creator Koutoulogenis, Giorgos S
Kokotou, Maroula G
Hayashi, Daiki
Mouchlis, Varnavas D
Dennis, Edward A
Kokotos, George
description 2-Oxoesters constitute an important class of potent and selective inhibitors of human cytosolic phospholipase A (GIVA cPLA ) 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 cPLA 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 cPLA . Both derivatives exhibited higher plasma stability in comparison with the unsubstituted compound and both derivatives inhibited GIVA cPLA , 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.
doi_str_mv 10.3390/biom10030491
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subjects Enzyme Stability
Esters - chemistry
Humans
Phospholipase A2 Inhibitors - chemistry
Phospholipases A2, Cytosolic - antagonists & inhibitors
Phospholipases A2, Cytosolic - chemistry
title 2-Oxoester Phospholipase A 2 Inhibitors with Enhanced Metabolic Stability
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