Discovery of γ-secretase inhibitors efficacious in a transgenic animal model of Alzheimer’s disease

• Published in: Bioorganic & medicinal chemistry letters 2007-01, Vol.17 (2), p.511-516
• Main Authors: Asberom, Theodros, Zhao, Zhiqiang, Bara, Thomas A., Clader, John W., Greenlee, William J., Hyde, Lynn A., Josien, Hubert B., Li, Wei, McPhail, Andrew T., Nomeir, Amin A., Parker, Eric M., Rajagopalan, Murali, Song, Lixin, Wong, Gwendolyn T., Zhang, Lili, Zhang, Qi, Pissarnitski, Dmitri A.
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Alzheimer’s disease; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid beta-Peptides - biosynthesis; Amyloid beta-Protein Precursor - metabolism; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Area Under Curve; Biological and medical sciences; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - therapeutic use; Humans; Indicators and Reagents; Kulinkovich reaction; Magnetic Resonance Spectroscopy; Medical sciences; Mice; Mice, Transgenic; Models, Molecular; Molecular Conformation; Neuropharmacology; Pharmacology. Drug treatments; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Rats; Structure-Activity Relationship; γ-Secretase inhibitors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2006.10.011

Attachment of the cyclopropylcarbamate group to the piperidine core of γ-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Aβ levels in TgCRND8 mice after a single PO dosing at 30 mpk.