4DI2

Crystal structure of BACE1 in complex with hydroxyethylamine inhibitor 37

4DI2 の概要

• エントリーDOI: 10.2210/pdb4di2/pdb
• 分子名称: Beta-secretase 1, (2R)-N-{(2S,3R)-4-{[(4'S)-6'-(2,2-dimethylpropyl)-3',4'-dihydrospiro[cyclobutane-1,2'-pyrano[2,3-b]pyridin]-4'-yl]amino}-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl}-2-methoxypropanamide, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: memapsin-2, alzheimer's disease, protease, beta-site amyloid precursor protein cleaving enzyme 1, app, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 3
• 化学式量合計: 139706.18

構造登録者

Whittington, D.A.,Long, A.M. (登録日: 2012-01-30, 公開日: 2012-10-10, 最終更新日: 2023-09-13)

主引用文献

Dineen, T.A.,Weiss, M.M.,Williamson, T.,Acton, P.,Babu-Khan, S.,Bartberger, M.D.,Brown, J.,Chen, K.,Cheng, Y.,Citron, M.,Croghan, M.D.,Dunn, R.T.,Esmay, J.,Graceffa, R.F.,Harried, S.S.,Hickman, D.,Hitchcock, S.A.,Horne, D.B.,Huang, H.,Imbeah-Ampiah, R.,Judd, T.,Kaller, M.R.,Kreiman, C.R.,La, D.S.,Li, V.,Lopez, P.,Louie, S.,Monenschein, H.,Nguyen, T.T.,Pennington, L.D.,San Miguel, T.,Sickmier, E.A.,Vargas, H.M.,Wahl, R.C.,Wen, P.H.,Whittington, D.A.,Wood, S.,Xue, Q.,Yang, B.H.,Patel, V.F.,Zhong, W.
Design and synthesis of potent, orally efficacious hydroxyethylamine derived beta-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.
J.Med.Chem., 55:9025-9044, 2012

PubMed Abstract: We have previously shown that hydroxyethylamines can be potent inhibitors of the BACE1 enzyme and that the generation of BACE1 inhibitors with CYP 3A4 inhibitory activities in this scaffold affords compounds (e.g., 1) with sufficient bioavailability and pharmacokinetic profiles to reduce central amyloid-β peptide (Aβ) levels in wild-type rats following oral dosing. In this article, we describe further modifications of the P1-phenyl ring of the hydroxyethylamine series to afford potent, dual BACE1/CYP 3A4 inhibitors which demonstrate improved penetration into the CNS. Several of these compounds caused robust reduction of Aβ levels in rat CSF and brain following oral dosing, and compound 37 exhibited an improved cardiovascular safety profile relative to 1.

PubMed: 22468684
DOI: 10.1021/jm300118s

実験手法

X-RAY DIFFRACTION (2 Å)