期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 17, 期 19, 页码 5428-5431出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2007.07.044
关键词
Alzheimer's disease; gamma-Secretase modulator; LXR agonist; gamma-Secretase inhibitor; aspartic protease; membrane protease
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. (C) 2007 Elsevier Ltd. All rights reserved.
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