Sawatzky, Edgar and Wehle, Sarah and Kling, Beata and Wendrich, Jan and Bringmann, Gerhard and Sotriffer, Christoph A. and Heilmann, Joerg and Decker, Michael (2016) Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode. JOURNAL OF MEDICINAL CHEMISTRY, 59 (5). pp. 2067-2082. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)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 (K-C = 14.3 nM) and also of hBChE (K-C = 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | AMYLOID-BETA-PEPTIDE; NITROGEN-BRIDGEHEAD COMPOUNDS; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; CHOLINESTERASE-INHIBITORS; CHOLESTEROL ESTERASE; HUMAN ACETYLCHOLINESTERASE; MOLECULAR RECOGNITION; BIOLOGICAL EVALUATION; GENETIC ALGORITHM; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Biology (Prof. Heilmann) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 26 Mar 2019 09:26 |
| Last Modified: | 26 Mar 2019 09:26 |
| URI: | https://pred.uni-regensburg.de/id/eprint/3252 |
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