2,6-Disubstituted N-arylsulfonyl piperidines as γ-secretase inhibitors

• Published in: Bioorganic & medicinal chemistry letters 2007, Vol.17 (1), p.57-62
• Main Authors: Pissarnitski, Dmitri A., Asberom, Theodros, Bara, Thomas A., Buevich, Alex V., Clader, John W., Greenlee, William J., Guzik, Henry S., Josien, Hubert B., Li, Wei, McEwan, Michael, McKittrick, Brian A., Nechuta, Terry L., Parker, Eric M., Sinning, Lisa, Smith, Elizabeth M., Song, Lixin, Vaccaro, Henry A., Voigt, Johannes H., Zhang, Lili, Zhang, Qi, Zhao, Zhiqiang
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Carbamate; Inhibitor; Inhibitory Concentration 50; Mosher ester; Piperidine; Piperidines - chemical synthesis; Piperidines - chemistry; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Stereoisomerism; Structure-Activity Relationship; Sulfonamide; γ-Secretase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.09.094

A novel piperidine series of γ-secretase inhibitors, potentially useful for the treatment of Alzheimer’s disease, is disclosed. A novel piperidine series of γ-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.