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

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.

• Authors: Rosana Leiva, Christian Griñan-Ferré, Constantí Seira, Elena Valverde, Andrew McBride, Margaret Binnie, Belén Pérez, F Javier Luque, Mercè Pallàs, Axel Bidon-Chanal, Scott P Webster, Santiago Vázquez
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 139 Pg. 412-428 (Oct 20 2017) ISSN: 1768-3254 [Electronic] France
• PMID: 28818766 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Chemical References

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

Topics

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