Aminobenzimidazoles and Structural Isomers as Templates for Dual-Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders

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• 作者：Dominik Dolles ; Martin Nimczick ; Matthias Scheiner ; Jacqueline Ramler ; Patricia Stadtm&#252 ; ller ; Edgar Sawatzky ; Antonios Drakopoulos ; Prof. Dr. Christoph Sotriffer ; Dr. Hans-Joachim Wittmann ; Dr. Andrea Strasser and Prof. Dr. Michael Decker
• 刊名：ChemMedChem
• 出版年：2016
• 出版时间：June 20, 2016
• 年：2016
• 卷：11
• 期：12
• 页码：1270-1283
• 全文大小：4904K
• ISSN：1860-7187

文摘

A pharmacophore model for butyrylcholinesterase (BChE) inhibitors was applied to a human cannabinoid subtype 2 receptor (hCB₂R) agonist and verified it as a first-generation lead for respective dual-acting compounds. The design, synthesis, and pharmacological evaluation of various derivatives led to the identification of aminobenzimidazoles as second-generation leads with micro- or sub-micromolar activities at both targets and excellent selectivity over hCB₁ and AChE, respectively. Computational studies of the first- and second-generation lead structures by applying molecular dynamics (MD) on the active hCB₂R model, along with docking and MD on hBChE, has enabled an explanation of their binding profiles at the protein levels and opened the way for further optimization. Dual-acting compounds with “balanced” affinities and excellent selectivities could be obtained that represent leads for treatment of both cognitive and pathophysiological impairment occurring in neurodegenerative disorders.