Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core
2010 (English)In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ISSN 0223-5234, Vol. 45, no 3, 870-882 p.Article in journal (Refereed) Published
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.
Alzheimers disease, BACE-1 inhibitors, Hydroxylethylene, Transition state isostere
National CategoryEngineering and Technology
IdentifiersURN: urn:nbn:se:liu:diva-54612DOI: 10.1016/j.ejmech.2009.11.013ISI: 000275404900003OAI: oai:DiVA.org:liu-54612DiVA: diva2:305991