title: ω-Imidazolyl- and ω-Tetrazolylalkylcarbamates as Inhibitors of Fatty Acid Amide Hydrolase: Biological Activity and in vitro Metabolic Stability.
abstract: Fatty acid amide hydrolase (FAAH) is a serine hydrolase that terminates the analgesic and anti-inflammatory effects of endocannabinoids such as anandamide. Herein, structure-activity relationship studies on a new series of aryl N-(ω-imidazolyl- and ω-tetrazolylalkyl)carbamate inhibitors of FAAH were investigated. As one result, a pronounced increase in inhibitory potency was observed if a phenyl residue attached to the carbamate oxygen atom was replaced by a pyridin-3-yl moiety. The most active compounds exhibited IC50 values in the low nanomolar range. In addition, investigations on the metabolic properties of these inhibitors were performed. In rat liver homogenate and in porcine plasma, the extent of their degradation was shown to be strongly dependent on the kind of aryl residue bound to the carbamate as well as on the length and type of the alkyl spacer connecting the carbamate group with the heterocyclic system. With the aid of esterase inhibitors it was shown that in porcine plasma, carboxylesterase-like enzymes and paraoxonase are involved in carbamate cleavage. Moreover, it was found that highly active pyridin-3-yl carbamates reacted with albumin, which led to covalent albumin adducts.
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, 48149, Münster, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Terwege
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, 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, 48149, Münster, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Garzinsky
authors.affiliation: Core Unit Proteomics, Interdisciplinary Center for Clinical Research (IZKF), University of Münster, Röntgenstrasse 21, 48149, Münster, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: König
authors.affiliation: Faculty of Chemistry and Chemical Biology, TU Dortmund University, Otto-Hahn-Strasse 6, 44227, Dortmund, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Koch
authors.affiliation: Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, 48149, Münster, Germany. lehrm@uni-muenster.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Lehr
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002219:Carbamates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008099:Liver / Q000378:metabolism; D062105:Molecular Docking Simulation; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013552:Swine; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D002219:Carbamates; D004791:Enzyme Inhibitors; D012709:Serum Albumin; D000099252:Fatty Acid Amide Hydrolases
keywords: albumin adducts; esterases; fatty acid amide hydrolase; inhibitors; metabolic stability