3IGB

Bace-1 with Compound 3

Summary for 3IGB

• Entry DOI: 10.2210/pdb3igb/pdb
• Descriptor: Beta-secretase 1, 8,8-diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (3 entities in total)
• Functional Keywords: bace-1, amino-imidazoles, inhibitors, 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: 46731.34

Authors

Olland, A.M. (deposition date: 2009-07-27, release date: 2009-11-03, Last modification date: 2024-10-09)

Primary citation

Malamas, M.S.,Erdei, J.,Gunawan, I.,Barnes, K.,Johnson, M.,Hui, Y.,Turner, J.,Hu, Y.,Wagner, E.,Fan, K.,Olland, A.,Bard, J.,Robichaud, A.J.
Aminoimidazoles as potent and selective human beta-secretase (BACE1) inhibitors
J.Med.Chem., 52:6314-6323, 2009

PubMed Abstract: The identification of small molecule aminoimidazoles as potent and selective human beta-secretase inhibitors is reported. These analogues demonstrate low nannomolar potency for BACE1 in a FRET assay, exhibit comparable activity in a cell-based (ELISA) assay, and show >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsin D, renin, and pepsin. Our design strategy was supported by molecular modeling studies based on the cocrystal structure of the HTS-hit 3 in the BACE1 active site. These strategies enabled us to integrate pyridine and pyrimidine groups on 3 extending deep into the S3 region of the BACE1 binding pocket and enhancing the ligand's potency. Compound (R)-37 displayed an IC50 value for BACE1 of 20 nM, cellular activity of 90 nM, and >100-fold selectivity over related aspartyl proteases. Acute oral administration of (R)-37 at 30 mg/kg resulted in a significant 71% reduction of plasma Abeta40 measured at the 6 h time point in a Tg2576 mouse model (p < 0.001).

PubMed: 19757823
DOI: 10.1021/jm9006752

Experimental method

X-RAY DIFFRACTION (2.238 Å)