Sawatzky_2016_J.Med.Chem_59_2067

Reference

Title : Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode - Sawatzky_2016_J.Med.Chem_59_2067
Author(s) : Sawatzky E , Wehle S , Kling B , Wendrich J , Bringmann G , Sotriffer CA , Heilmann J , Decker M
Ref : Journal of Medicinal Chemistry , 59 :2067 , 2016
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.

PubMedSearch : Sawatzky_2016_J.Med.Chem_59_2067
PubMedID: 26886849

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Citations formats

Sawatzky E, Wehle S, Kling B, Wendrich J, Bringmann G, Sotriffer CA, Heilmann J, Decker M (2016)
Discovery of Highly Selective and Nanomolar Carbamate-Based Butyrylcholinesterase Inhibitors by Rational Investigation into Their Inhibition Mode
Journal of Medicinal Chemistry 59 :2067

Sawatzky E, Wehle S, Kling B, Wendrich J, Bringmann G, Sotriffer CA, Heilmann J, Decker M (2016)
Journal of Medicinal Chemistry 59 :2067