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Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology. Linköping University, The Institute of Technology.
Linköping University, Department of Physics, Chemistry and Biology, Organic Chemistry . Linköping University, The Institute of Technology.
Medivir AB.
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2010 (English)In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ISSN 0223-5234, Vol. 45, no 3, 870-882 p.Article in journal (Refereed) Published
Abstract [en]

We herein describe the design and synthesis of a series of BACE-1 inhibitors incorporating a P1-substituted hydroxyl ethylene transition state isostere. The synthetic route starting from commercially available carbohydrates yielded a pivotal lactone intermediate with excellent stereochemical control which subsequently could be diversified at the PI-position. The final inhibitors were optimized using three different amines to provide the residues in the P2-P3 position and three different acids affording the residues in the P2-P3 position. In addition we report on the stereochemical preference of the P1-methyl substituent in the synthesized inhibitors. All inhibitors were evaluated in an in vitro BACE-I assay where the most potent inhibitor, 34-(R), exhibited a BACE-1 IC50 Value of 3.1 nM.

Place, publisher, year, edition, pages
2010. Vol. 45, no 3, 870-882 p.
Keyword [en]
Alzheimers disease, BACE-1 inhibitors, Hydroxylethylene, Transition state isostere
National Category
Engineering and Technology
Identifiers
URN: urn:nbn:se:liu:diva-54612DOI: 10.1016/j.ejmech.2009.11.013ISI: 000275404900003OAI: oai:DiVA.org:liu-54612DiVA: diva2:305991
Available from: 2010-03-26 Created: 2010-03-26 Last updated: 2010-03-26

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Wångsell, FredrikGustafsson, KarinKvarnström, Ingemar

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Organic Chemistry The Institute of TechnologyDepartment of Physics, Chemistry and Biology
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