Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core
2010 (English)In: European Journal of Medicinal Chemistry, ISSN 0223-5234, E-ISSN 1768-3254, 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 hydroxylethylene 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 P1-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-1 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.
Alzheimer's disease, BACE-1 inhibitors, Hydroxylethylene, Transition state isostere
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-109028DOI: 10.1016/j.ejmech.2009.11.013ISI: 000275404900003PubMedID: 20036448OAI: oai:DiVA.org:uu-109028DiVA: diva2:242291