2-Oxoester Phospholipase A₂ Inhibitors with Enhanced Metabolic Stability.

ABSTRACT: 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 ?-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 ?-carbon atom to the oxoester functionality exhibits enhancement of the metabolic stability and retains considerable inhibitory potency.

SUBMITTER: Koutoulogenis GS 

PROVIDER: S-EPMC7175278 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature