Conversion of the LXR-agonist TO-901317—From inverse to normal modulation of γ-secretase by addition of a carboxylic acid and a lipophilic anchor

Bioorganic & Medicinal Chemistry Letters
2007.0

Abstract

TO-901317, a LXR agonist, is an inverse modulator of Alzheimer's disease associated gamma-secretase. We synthesized TO-901317 analogous compound but replaced the hexafluorocarbinol moiety by an oxyacetic acid functionality and hypothesized that the replacement would change the mode of action from an inverse modulation to normal modulation of gamma-secretase. As anticipated, acid 9 was found to be an effective modulator of gamma-secretase and displayed activity at low micromolar concentration. This significant modification can be applied to several inverse gamma-secretase modulators. Such modulators may preserve the cleavage of other gamma-secretase substrates such as Notch.

Knowledge Graph

Similar Paper

Conversion of the LXR-agonist TO-901317—From inverse to normal modulation of γ-secretase by addition of a carboxylic acid and a lipophilic anchor
Bioorganic & Medicinal Chemistry Letters 2007.0
SAR studies of acidic dual γ-secretase/PPARγ modulators
Bioorganic & Medicinal Chemistry 2011.0
Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity
Journal of Medicinal Chemistry 2010.0
Synthesis and evaluation of anilinohexafluoroisopropanols as activators/modulators of LXRα and β
Bioorganic & Medicinal Chemistry Letters 2006.0
Discovery and optimization of a novel series of liver X receptor-α agonists
Bioorganic & Medicinal Chemistry Letters 2006.0
Structure-based design of substituted hexafluoroisopropanol-arylsulfonamides as modulators of RORc
Bioorganic & Medicinal Chemistry Letters 2013.0
Design, synthesis and pharmacology of 1,1-bistrifluoromethylcarbinol derivatives as liver X receptor β-selective agonists
Bioorganic & Medicinal Chemistry Letters 2015.0
Indazole-Based Liver X Receptor (LXR) Modulators with Maintained Atherosclerotic Lesion Reduction Activity but Diminished Stimulation of Hepatic Triglyceride Synthesis
Journal of Medicinal Chemistry 2008.0
Identification and in Vivo Evaluation of Liver X Receptor β-Selective Agonists for the Potential Treatment of Alzheimer’s Disease
Journal of Medicinal Chemistry 2016.0
Development of novel liver X receptor modulators based on a 1,2,4-triazole scaffold
Bioorganic & Medicinal Chemistry Letters 2019.0