3INE

Bace1 with the aminohydantoin Compound S-34

Summary for 3INE

• Entry DOI: 10.2210/pdb3ine/pdb
• Related: 3IND 3INF 3INH
• Descriptor: Beta-secretase 1, (5S)-2-amino-5-(4-methoxy-3-methylphenyl)-3-methyl-5-[(3S,5S,7S)-tricyclo[3.3.1.1~3,7~]dec-1-yl]-3,5-dihydro-4H-imidazol-4-one (3 entities in total)
• Functional Keywords: bace1, xray, inhibitor, alternative splicing, aspartyl protease, disulfide bond, glycoprotein, hydrolase, membrane, polymorphism, protease, transmembrane, zymogen
• Biological source: Homo sapiens (human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 46808.47

Authors

Olland, A.M.,Chopra, R. (deposition date: 2009-08-12, release date: 2010-03-02, Last modification date: 2024-10-16)

Primary citation

Malamas, M.S.,Erdei, J.,Gunawan, I.,Turner, J.,Hu, Y.,Wagner, E.,Fan, K.,Chopra, R.,Olland, A.,Bard, J.,Jacobsen, S.,Magolda, R.L.,Pangalos, M.,Robichaud, A.J.
Design and synthesis of 5,5'-disubstituted aminohydantoins as potent and selective human beta-secretase (BACE1) inhibitors.
J.Med.Chem., 53:1146-1158, 2010

PubMed Abstract: The identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC(50) value for BACE1 of 10 nM and exhibited comparable cellular activity (EC(50) = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (p < 0.001).

PubMed: 19968289
DOI: 10.1021/jm901414e

Experimental method

X-RAY DIFFRACTION (1.996 Å)