The discovery of fused oxadiazepines as gamma secretase modulators for treatment of Alzheimer's disease.

Abstract

In an attempt to further improve overall profiles of the oxadiazine series of GSMs, in particular the hERG activity, conformational modifications of the core structure resulted in the identification of fused oxadiazepines such as 7i which had an improved hERG inhibition profile and was a highly efficacious GSM in vitro and in vivo in rats. These SAR explorations offer opportunities to identify potential drugs to treat Alzheimer's disease.

• Authors: Hongmei Li, Jun Qin, Pawan Dhondi, Wei Zhou, Monica Vicarel, Thomas Bara, David Cole, Hubert Josien, Dmitri Pissarnitski, Zhaoning Zhu, Anandan Palani, Robert Aslanian, John Clader, Michael Czarniecki, William Greenlee, Mary Cohen-Williams, Lynn Hyde, Lixin Song, Lili Zhang, Inhou Chu, Xianhai Huang
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 23 Issue 2 Pg. 466-71 (Jan 15 2013) ISSN: 1464-3405 [Electronic] England
• PMID: 23253441 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Azepines
• ERG1 Potassium Channel
• Enzyme Inhibitors
• Ether-A-Go-Go Potassium Channels
• KCNH2 protein, human
• Amyloid Precursor Protein Secretases

Topics

• Alzheimer Disease (drug therapy)
• Amyloid Precursor Protein Secretases (metabolism)
• Animals
• Azepines (chemical synthesis, chemistry, pharmacology)
• Drug Discovery
• ERG1 Potassium Channel
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (chemistry, pharmacology)
• Ether-A-Go-Go Potassium Channels (antagonists & inhibitors)
• Humans
• Inhibitory Concentration 50
• Molecular Structure
• Rats
• Structure-Activity Relationship