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

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...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2007-01, Vol.17 (2), p.511-516
Hauptverfasser:	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:	Artikel
Sprache:	eng
Schlagworte:	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
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Zusammenfassung:	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.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2006.10.011