Inhibition of the BACE-1 protease enzyme has over the recent decade developed into a promising drug strategy for Alzheimer therapy. In this report, more than 20 new BACE-1 protease inhibitors based on α-phenylnorstatine, α-benzylnorstatine, iso-serine, and β-alanine moieties have been prepared. The inhibitors were synthesized by applying Fmoc solid phase methodology and evaluated for their inhibitory properties. The most potent inhibitor, tert-alcohol containing (R)-12 (IC50 = 0.19 μM) was co-crystallized in the active site of the BACE-1 protease, furnishing a novel binding mode in which the N-terminal amine makes a hydrogen bond to one of the catalytic aspartic acids. © 2010 Elsevier Ltd. All rights reserved.
CITATION STYLE
Wngsell, F., Nordeman, P., Sävmarker, J., Emanuelsson, R., Jansson, K., Lindberg, J., … Larhed, M. (2011). Investigation of α-phenylnorstatine and α-benzylnorstatine as transition state isostere motifs in the search for new BACE-1 inhibitors. Bioorganic and Medicinal Chemistry, 19(1), 145–155. https://doi.org/10.1016/j.bmc.2010.11.042
Mendeley helps you to discover research relevant for your work.