Part 3: Notch-sparing γ-secretase inhibitors: SAR studies of 2-substituted aminopyridopyrimidinones

• Published in: Bioorganic & medicinal chemistry letters Vol. 26; no. 9; pp. 2138 - 2141
• Main Authors: Zhang, Jing, Lu, Dai, Wei, Han-Xun, Gu, Yongli, Selkoe, Dennis J., Wolfe, Michael S., Augelli-Szafran, Corinne E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-05-2016
• Subjects: Alzheimer’s disease; Aminopyridopyrimidines; Amyloid beta-Peptides - antagonists & inhibitors; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Animals; Aβ production; Humans; Microsomes, Liver - metabolism; Notch-processing; Peptide Fragments - antagonists & inhibitors; Protease Inhibitors - chemical synthesis; Protease Inhibitors - pharmacology; Pyridones - chemical synthesis; Pyridones - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Rats; Receptor, Notch1 - metabolism; Structure-Activity Relationship; γ-Secretase inhibitors; Aminopyridopyrimidines; Notch-processing; γ-Secretase inhibitors; Alzheimer’s disease; Aβ production
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2016.03.077

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In search for novel lead compounds as γ-secretase inhibitors, analogs of aminopyrido[2,3-d]pyrimidin-7-ones (I) were synthesized and evaluated for inhibitory effects on amyloid-β-peptide production and cleavage of the Notch1 receptor mediated by γ-secretase. Selected pyridopyrimidines, such as 1, 8, 9, 10, 11 and 16 are γ-secretase inhibitors that did not have an effect on Notch1 receptor processing.