title: Conversion of the LXR-agonist TO-901317--from inverse to normal modulation of gamma-secretase by addition of a carboxylic acid and a lipophilic anchor.
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.
authors.affiliation: Clemens Schöpf-Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstr. 22, D-64287 Darmstadt, Germany.
authors.forename: Rajeshwar
authors.initials: R
authors.lastname: Narlawar
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Baumann
authors.forename: Christian
authors.initials: C
authors.lastname: Czech
authors.forename: Boris
authors.initials: B
authors.lastname: Schmidt
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000819:agonists*; D004305:Dose-Response Relationship, Drug; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D053829:Amyloid Precursor Protein Secretases; D002264:Carboxylic Acids; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D007202:Indicators and Reagents; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides