3IXK

Potent beta-secretase 1 inhibitor

Summary for 3IXK

• Entry DOI: 10.2210/pdb3ixk/pdb
• Descriptor: Beta-secretase 1, N-[(2S,3S,5R)-1-[(3,5-difluorophenyl)methoxy]-3-hydroxy-5-methyl-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, statine, inhibitor, aspartyl protease, glycoprotein, hydrolase, membrane, protease, transmembrane, zymogen, disulfide bond
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 3
• Total formula weight: 138344.61

Authors

Borkakoti, N.,Lindberg, J.D.,Nystrom, S. (deposition date: 2009-09-04, release date: 2010-09-08, Last modification date: 2024-10-30)

Primary citation

Wangsell, F.,Gustafsson, K.,Kvarnstrom, I.,Borkakoti, N.,Edlund, M.,Jansson, K.,Lindberg, J.,Hallberg, A.,Rosenquist, A.,Samuelsson, B.
Synthesis of potent BACE-1 inhibitors incorporating a hydroxyethylene isostere as central core.
Eur.J.Med.Chem., 45:870-882, 2010

PubMed Abstract: 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 IC(50) value of 3.1 nM.

PubMed: 20036448
DOI: 10.1016/j.ejmech.2009.11.013

Experimental method

X-RAY DIFFRACTION (2.5 Å)