2,6-Disubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitors.

Abstract

A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.

• Authors: Dmitri A Pissarnitski, Theodros Asberom, Thomas A Bara, Alex V Buevich, John W Clader, William J Greenlee, Henry S Guzik, Hubert B Josien, Wei Li, Michael McEwan, Brian A McKittrick, Terry L Nechuta, Eric M Parker, Lisa Sinning, Elizabeth M Smith, Lixin Song, Henry A Vaccaro, Johannes H Voigt, Lili Zhang, Qi Zhang, Zhiqiang Zhao
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 17 Issue 1 Pg. 57-62 (Jan 01 2007) ISSN: 0960-894X [Print] England
• PMID: 17055268 (Publication Type: Journal Article)

Chemical References

• Piperidines
• Protease Inhibitors
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (drug therapy)
• Amyloid Precursor Protein Secretases (antagonists & inhibitors)
• Inhibitory Concentration 50
• Piperidines (chemical synthesis, chemistry)
• Protease Inhibitors (chemical synthesis, chemistry)
• Stereoisomerism
• Structure-Activity Relationship