Discovery, Biological Evaluation, and Crystal Structure of a Novel Nanomolar Selective Butyrylcholinesterase Inhibitor

作者：Brus Boris; Kosak Urban; Turk Samo; Pislar Anja; Coquelle Nicolas; Kos Janko; Stojan Jure; Colletier Jacques Philippe; Gobec Stanislav^*

来源：Journal of Medicinal Chemistry, 2014, 57(19): 8167-8179.

DOI：10.1021/jm501195e

Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The most potent compound 1 (IC50 = 21.3 nM) was resynthesized and resolved into its pure enantiomers. A high degree of stereoselective activity was revealed and a dissociation constant of 2.7 nM was determined for the most potent steroisomer (+)-1. The crystal structure of human BChE in complex with compound (+)-1 was solved revealing the binding mode and providing clues for potential optimization additionally,compound 1 inhibited amyloid (beta)1-42 peptide self-induced aggregation into fibrils (by 61.7% at 10 mu M) and protected cultured SH-SYSY cells against amyloid-beta-induced toxicity. These data suggest that compound 1 represents a promising candidate for hit to-lead follow up in the drug-discovery process against Alzheimer's disease

• 出版日期2014-10-9
• 单位中国地震局