1-Indol-1-yl-propan-2-ones and related heterocyclic compounds as dual inhibitors of cytosolic phospholipase A(2)alpha and fatty acid amide hydrolase.

Laura Forster, Joachim Ludwig, Martina Kaptur, Stefanie Bovens, Alwine Schulze Elfringhoff, Angela Holtfrerich, Matthias Lehr

Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.

Bioorganic & medicinal chemistry 2010 Jan 15

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Cytosolic phospholipase A(2)alpha (cPLA(2)alpha) and fatty acid amide hydrolase (FAAH) are enzymes, which have emerged as attractive targets for the development of analgetic and anti-inflammatory drugs. We recently reported that 1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (10) and related compounds are inhibitors of cPLA(2)alpha. Since cPLA(2)alpha and FAAH possess several common structural features, we now screened this substance series together with some new derivatives for FAAH inhibition. Some of the assayed compounds proved to be selective cPLA(2)alpha inhibitors, while others showed high FAAH and moderate cPLA(2)alpha inhibitory potency. Furthermore, several derivatives were favorably active against both enzymes and, therefore, could represent agents, which have improved analgetic and anti-inflammatory qualities in comparison with selective cPLA(2)alpha and FAAH inhibitors. Copyright 2009 Elsevier Ltd. All rights reserved.

Citation

Laura Forster, Joachim Ludwig, Martina Kaptur, Stefanie Bovens, Alwine Schulze Elfringhoff, Angela Holtfrerich, Matthias Lehr. 1-Indol-1-yl-propan-2-ones and related heterocyclic compounds as dual inhibitors of cytosolic phospholipase A(2)alpha and fatty acid amide hydrolase. Bioorganic & medicinal chemistry. 2010 Jan 15;18(2):945-52