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1‐(3‐Biaryloxy‐2‐oxopropyl)indole‐5‐carboxylic Acids and Related Compounds as Dual Inhibitors of Human Cytosolic Phospholipase A 2 α and Fatty Acid Amide Hydrolase
Author(s) -
Zahov Stefan,
Drews Andreas,
Hess Mark,
Schulze Elfringhoff Alwine,
Lehr Matthias
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000473
Subject(s) - fatty acid amide hydrolase , phospholipase a2 , chemistry , indole test , carboxylic acid , phospholipase a , enzyme , stereochemistry , moiety , amide , biochemistry , phospholipase , antagonist , receptor , cannabinoid receptor
Cytosolic phospholipase A 2 α (cPLA 2 α) and fatty acid amide hydrolase (FAAH) are enzymes that have emerged as attractive targets for the development of analgesic and anti‐inflammatory drugs. We recently reported that 1‐[3‐(4‐octylphenoxy)‐2‐ oxopropyl]indole‐5‐carboxylic acid ( 5 ) is a dual inhibitor of cPLA 2 α and FAAH. Structure–activity relationship studies revealed that substituents at the indole 3‐ and 5‐positions and replacement of the indole scaffold of this compound by other heterocycles strongly influences the inhibitory potency against cPLA 2 α and FAAH, respectively. Herein we report the effect of variation of the 4‐octyl residue of 5 and an exchange of its carboxylic acid moiety by some bioisosteric functional groups. Several of the compounds assayed were favorably active against both enzymes, and could therefore represent agents with improved analgesic and anti‐inflammatory qualities in comparison with selective cPLA 2 α and FAAH inhibitors.