Abstract
Novel BACE-1 inhibitors with a hydroxyethylene central core have been developed. Modified P1´ and extended P1 substituents were incorporated with the aim to explore potential interactions with the S1´ and the S1-S3 pocket, respectively, of BACE-1. Inhibitors were identified displaying IC50 values in the nanomolar range, i.e. 69 nM for the most potent compound. Possible inhibitor interactions with the enzyme are also discussed.
Highlights
Alzheimer’s disease (AD) is a serious and fatal condition affecting tens of millions of individuals worldwide [1]
Earlier studies of aspartic proteases such as the malaria plasmepsins [5] and human renin [6] have shown that the S1 pocket of these enzymes can accommodate large P1 residues, many of which can reach into the S3 pocket
R4 amines M-O were synthesized from commercially available precursors using standard coupling and deprotection procedures and amine P was synthesized from commercially available precursors according to a three step protocol
Summary
Alzheimer’s disease (AD) is a serious and fatal condition affecting tens of millions of individuals worldwide [1]. This form of dementia is primarily believed to be caused by the formation of insoluble polypeptides which form neurodegenerative plaques within the brain. One of the key enzymes involved in this formation is the human aspartic protease BACE-1 [2]. This knowledge together with the fact that no amyloid plaques are found in knock-out mice lacking BACE-1, while they seem to be vital and fertile, make inhibition of BACE-1 an interesting approach for targeting AD [3, 4]. Some of these inhibitors displayed substantial activity against BACE-1 (12-40 nM), in the enzyme assay, but they were found to be inactive in a cell-based assay, likely due to poor permeability
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