Purine derivatives as potent γ-secretase modulators

The development of a novel series of purines as γ-secretase modulators for potential use in the treatment of Alzheimer’s disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based γ-secretase modulators with 300- to 2000-fold in vit...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2010-04, Vol.20 (7), p.2279-2282
Main Authors: Rivkin, Alexey, Ahearn, Sean P., Chichetti, Stephanie M., Hamblett, Christopher L., Garcia, Yudith, Martinez, Michelle, Hubbs, Jed L., Reutershan, Michael H., Daniels, Matthew H., Siliphaivanh, Phieng, Otte, Karin M., Li, Chaomin, Rosenau, Andrew, Surdi, Laura M., Jung, Joon, Hughes, Bethany L., Crispino, Jamie L., Nikov, George N., Middleton, Richard E., Moxham, Christopher M., Szewczak, Alexander A., Shah, Sanjiv, Moy, Lily Y., Kenific, Candia M., Tanga, Flobert, Cruz, Jonathan C., Andrade, Paula, Angagaw, Minilik H., Shomer, Nirah H., Miller, Thomas, Munoz, Benito, Shearman, Mark S.
Format: Article
Language:English
Subjects:
Alzheimer Disease - drug therapy
Amyloid beta-Peptides - antagonists & inhibitors
Amyloid beta-Peptides - metabolism
Amyloid Precursor Protein Secretases - genetics
Amyloid Precursor Protein Secretases - metabolism
Animals
Biological and medical sciences
Humans
Medical sciences
Mice
Mice, Transgenic
Neuropharmacology
Peptide Fragments - antagonists & inhibitors
Peptide Fragments - metabolism
Pharmacology. Drug treatments
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Purines - chemistry
Purines - pharmacology
Purines - therapeutic use
Receptors, Notch - metabolism
Structure-Activity Relationship
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Description
Summary:The development of a novel series of purines as γ-secretase modulators for potential use in the treatment of Alzheimer’s disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based γ-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Αβ42 in an APP-YAC transgenic mouse model. The development of a novel series of purines as γ-secretase modulators for potential use in the treatment of Alzheimer’s disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based γ-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Αβ42 in an APP-YAC transgenic mouse model.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2010.02.008