Design, synthesis and in?vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction

摘要

Abstract Recent findings suggest that treatment with 11β-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11β-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease. Graphical abstract Display Omitted Highlights ? Several pyrrolidine-based polycyclic amides are prepared as 11β-HSD1 inhibitors. ? Amides are synthesized by coupling of pyrrolidines with carboxylic acids. ? The more potent compounds present low nanomolar IC 50 . ? A candidate is administered to old SAMP8 mice for four weeks. ? The treatment prevents memory deficits and displays a neuroprotective action.