title: 1-Heteroarylpropan-2-ones as inhibitors of fatty acid amide hydrolase: Studies on structure-activity relationships and metabolic stability.
abstract: The serine hydrolase fatty acid amide hydrolase (FAAH) catalyzes the degradation of the endocannabinoid anandamide, which possesses analgesic and anti-inflammatory effects. A new series of 1-heteroarylpropan-2-ones was synthesized and evaluated for FAAH inhibition. Structure-activity relationship studies revealed that 1H-benzotriazol-1-yl, 1H-7-azabenzotriazol-1-yl, 1H-tetrazol-1-yl and 2H-tetrazol-2-yl substituents have the highest impact on inhibitory potency. Furthermore, attempts were made to increase the limited metabolic stability of the ketone functionality of these compounds towards metabolic reduction by introduction of shielding alkyl substituents in proximity of this serine reactive group.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, D-48149 Münster, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zahov
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, D-48149 Münster, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Garzinsky
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, D-48149 Münster, Germany.
authors.forename: Walburga
authors.initials: W
authors.lastname: Hanekamp
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, D-48149 Münster, Germany. Electronic address: lehrm@uni-muenster.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004795:Enzyme Stability / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D011407:Propane / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D011407:Propane; D000099252:Fatty Acid Amide Hydrolases
keywords: Aqueous solubility; Enzyme inhibition; Fatty acid amide hydrolase; Metabolic stability; Propan-2-one