title: 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.
abstract: 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.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Hittorfstrasse 58-62, D-48149 Münster, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Forster
authors.forename: Joachim
authors.initials: J
authors.lastname: Ludwig
authors.forename: Martina
authors.initials: M
authors.lastname: Kaptur
authors.forename: Stefanie
authors.initials: S
authors.lastname: Bovens
authors.forename: Alwine Schulze
authors.initials: AS
authors.lastname: Elfringhoff
authors.forename: Angela
authors.initials: A
authors.lastname: Holtfrerich
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D054513:Group IV Phospholipases A2; D006571:Heterocyclic Compounds; D007211:Indoles; D000099252:Fatty Acid Amide Hydrolases; C548737:1-indol-1-yl-propan-2-one