title: Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode.
abstract: Butyrylcholinesterase (BChE) is a promising target for the treatment of later stage cognitive decline in Alzheimer's disease. A set of pseudo-irreversible BChE inhibitors with high selectivity over hAChE was synthesized based on carbamates attached to tetrahydroquinazoline scaffolds with the 2-thiophenyl compound 2p as the most potent inhibitor of eqBChE (KC = 14.3 nM) and also of hBChE (KC = 19.7 nM). The inhibitors transfer the carbamate moiety onto the active site under release of the phenolic tetrahydroquinazoline scaffolds that themselves act as neuroprotectants. By combination of kinetic data with molecular docking studies, a plausible binding model was probed describing how the tetrahydroquinazoline scaffold guides the carbamate into a close position to the active site. The model explains the influence of the carrier scaffold onto the affinity of an inhibitor just before carbamate transfer. This strategy can be used to utilize the binding mode of other carbamate-based inhibitors.
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg , Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Sawatzky
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg , Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wehle
authors.affiliation: Lehrstuhl für Pharmazeutische Biologie, Institut für Pharmazie, Universität Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Beata
authors.initials: B
authors.lastname: Kling
authors.affiliation: Lehrstuhl für Organische Chemie I, Institut für Organische Chemie, Universität Würzburg , Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Wendrich
authors.affiliation: Lehrstuhl für Organische Chemie I, Institut für Organische Chemie, Universität Würzburg , Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bringmann
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg , Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Sotriffer
authors.affiliation: Lehrstuhl für Pharmazeutische Biologie, Institut für Pharmazie, Universität Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.affiliation: Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Universität Würzburg , Am Hubland, D-97074 Würzburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism*; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D002800:Cholinesterase Inhibitors; D002091:Butyrylcholinesterase