1067648-53-6Relevant articles and documents
Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core
W?ngsell, Fredrik,Gustafsson, Karin,Kvarnstr?m, Ingemar,Borkakoti, Neera,Edlund, Michael,Jansson, Katarina,Lindberg, Jimmy,Hallberg, Anders,Rosenquist, ?sa,Samuelsson, Bertil
, p. 870 - 882 (2010)
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.
