| 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. | |
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MedLine Citation:
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PMID: 17723298 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Rajeshwar Narlawar; Karlheinz Baumann; Christian Czech; Boris Schmidt |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2007-08-06 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry letters Volume: 17 ISSN: 0960-894X ISO Abbreviation: Bioorg. Med. Chem. Lett. Publication Date: 2007 Oct |
Date Detail:
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Created Date: 2007-09-18 Completed Date: 2007-11-27 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9107377 Medline TA: Bioorg Med Chem Lett Country: England |
Other Details:
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Languages: eng Pagination: 5428-31 Citation Subset: IM |
Affiliation:
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Clemens Schöpf-Institute of Chemistry and Biochemistry, Darmstadt University of Technology, Petersenstr. 22, D-64287 Darmstadt, Germany. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amyloid Precursor Protein Secretases
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antagonists & inhibitors* Carboxylic Acids / chemical synthesis*, pharmacology* Cell Survival / drug effects DNA-Binding Proteins / agonists* Dose-Response Relationship, Drug Hydrocarbons, Fluorinated / chemical synthesis*, pharmacology* Indicators and Reagents Orphan Nuclear Receptors Receptors, Cytoplasmic and Nuclear / agonists* Structure-Activity Relationship Sulfonamides / chemical synthesis*, pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/Carboxylic Acids; 0/DNA-Binding Proteins; 0/Hydrocarbons, Fluorinated; 0/Indicators and Reagents; 0/Orphan Nuclear Receptors; 0/Receptors, Cytoplasmic and Nuclear; 0/Sulfonamides; 0/TO-901317; 0/liver X receptor; EC 3.4.-/Amyloid Precursor Protein Secretases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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