Design and synthesis of bicyclic heterocycles as potent γ-secretase modulators

The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer’s drug which demonstrated high in vitro and in vivo potency against Aβ42 peptide, reduced lipophilicity and enhanc...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-09, Vol.23 (17), p.4794-4800
Hauptverfasser:	Oehlrich, Daniel, Rombouts, Frederik J.R., Berthelot, Didier, Bischoff, François P., De Cleyn, Michel A.J., Jaroskova, Libuse, Macdonald, Gregor, Mercken, Marc, Surkyn, Michel, Trabanco, Andrés A., Tresadern, Gary, Van Brandt, Sven, Velter, Adriana I., Wu, Tongfei, Gijsen, Harrie J.M.
Format:	Artikel
Sprache:	eng
Schlagworte:	Alzheimer Disease - drug therapy Alzheimer Disease - enzymology Alzheimer’s disease Amyloid Precursor Protein Secretases - metabolism Animals brain Bridged Bicyclo Compounds, Heterocyclic - chemistry Bridged Bicyclo Compounds, Heterocyclic - metabolism Bridged Bicyclo Compounds, Heterocyclic - pharmacology Dogs Drug Design drugs Humans hydrophobicity Mice Microsomes, Liver - metabolism Models, Molecular Piperidines - chemistry Piperidines - metabolism Piperidines - pharmacology Triazoles - chemistry Triazoles - metabolism Triazoles - pharmacology γ-Secretase modulators
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Zusammenfassung:	The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer’s drug which demonstrated high in vitro and in vivo potency against Aβ42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.06.100