3IGB

Bace-1 with Compound 3

3IGB の概要

• エントリーDOI: 10.2210/pdb3igb/pdb
• 分子名称: Beta-secretase 1, 8,8-diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (3 entities in total)
• 機能のキーワード: bace-1, amino-imidazoles, inhibitors, alternative splicing, aspartyl protease, disulfide bond, glycoprotein, hydrolase, membrane, polymorphism, protease, transmembrane, zymogen
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Membrane; Single-pass type I membrane protein: P56817
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46731.34

構造登録者

Olland, A.M. (登録日: 2009-07-27, 公開日: 2009-11-03, 最終更新日: 2024-10-09)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.238 Å)