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

Eur J Med Chem. 2017 Oct 20:139:412-428. doi: 10.1016/j.ejmech.2017.08.003. Epub 2017 Aug 4.

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.

Keywords: 11β-HSD1 inhibitors; Adamantane; Aged-related cognitive dysfunction; Alzheimer's disease; Drug design; Glucocorticoids; Polycyclic substituents; SAMP8 mouse.

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / antagonists & inhibitors*
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / metabolism
  • Age Factors
  • Animals
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Structure
  • Pyrrolidines / chemical synthesis
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyrrolidines
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • pyrrolidine