3I25

Potent Beta-Secretase 1 hydroxyethylene Inhibitor

Summary for 3I25

• Entry DOI: 10.2210/pdb3i25/pdb
• Descriptor: Beta-secretase 1, N-[(2S,3S,5R)-1-(3,5-difluorophenoxy)-3-hydroxy-5-(2-methoxyethoxy)-6-[[(2S)-3-methyl-1-oxo-1-(phenylmethylamino)butan-2-yl]amino]-6-oxo-hexan-2-yl]-5-(methyl-methylsulfonyl-amino)-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide (3 entities in total)
• Functional Keywords: bace, beta-secretase, inhibitor, aspartyl protease, protease, alternative splicing, disulfide bond, glycoprotein, hydrolase, membrane, polymorphism, transmembrane, zymogen
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 3
• Total formula weight: 138876.27

Authors

Lindberg, J.D.,Borkakoti, N.,Nystrom, S. (deposition date: 2009-06-29, release date: 2010-06-02, Last modification date: 2024-10-09)

Primary citation

Bjorklund, C.,Adolfsson, H.,Jansson, K.,Lindberg, J.,Vrang, L.,Hallberg, A.,Rosenquist, A.,Samuelsson, B.
Discovery of potent BACE-1 inhibitors containing a new hydroxyethylene (HE) scaffold: exploration of P1' alkoxy residues and an aminoethylene (AE) central core
Bioorg.Med.Chem., 18:1711-1723, 2010

PubMed Abstract: In a preceding study we have described the development of a new hydroxyethylene (HE) core motif displaying P1 aryloxymethyl and P1' methoxy substituents delivering potent BACE-1 inhibitors. In a continuation of this work we have now explored the SAR of the S1' pocket by introducing a set of P1' alkoxy groups and evaluated them as BACE-1 inhibitors. Previously the P1 and P1' positions of the classical HE template have been relatively little explored due to the complexity of the chemical routes involved in modifications at these positions. However, the chemistries developed for the current HE template renders substituents in both the P1 and P1' positions readily available for SAR exploration. The BACE-1 inhibitors prepared displayed K(i) values in the range of 1-20 nM, where the most potent compounds featured small P1' groups. The cathepsin D selectivity which was high for the smallest P1' substituents (P1'=ethoxy, fold selectively >1500) dropped for larger groups (P1'=benzyloxy, fold selectivity of 3). We have also confirmed the importance of both the hydroxyl group and its stereochemistry preference for this HE transition state isostere by preparing both the deoxygenated analogue and by inverting the configuration of the hydroxyl group to the R-configuration, which as expected resulted in large activity drops. Finally substituting the hydroxyl group by an amino group having the same configuration (S), which previously have been described to deliver potent BACE-1 inhibitors with advantageous properties, surprisingly resulted in a large drop in the inhibitory activity.

PubMed: 20122837
DOI: 10.1016/j.bmc.2009.12.051

Experimental method

X-RAY DIFFRACTION (2.1 Å)