4WTU

Crystal structure of BACE1 in complex with 2-aminooxazoline 3-aza-4-fluoro-xanthene inhibitor 22

4WTU の概要

• エントリーDOI: 10.2210/pdb4wtu/pdb
• 関連するPDBエントリー: 4RCD 4RCE 4RCF
• 分子名称: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (5 entities in total)
• 機能のキーワード: aspartic protease, amyloid precursor protein, alzheimer's disease, 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: 1
• 化学式量合計: 46962.67

構造登録者

Whittington, D.A.,Long, A.M. (登録日: 2014-10-30, 公開日: 2015-03-04, 最終更新日: 2024-10-30)

主引用文献

Cheng, Y.,Brown, J.,Judd, T.C.,Lopez, P.,Qian, W.,Powers, T.S.,Chen, J.J.,Bartberger, M.D.,Chen, K.,Dunn, R.T.,Epstein, O.,Fremeau, R.T.,Harried, S.,Hickman, D.,Hitchcock, S.A.,Luo, Y.,Minatti, A.E.,Patel, V.F.,Vargas, H.M.,Wahl, R.C.,Weiss, M.M.,Wen, P.H.,White, R.D.,Whittington, D.A.,Zheng, X.M.,Wood, S.
An Orally Available BACE1 Inhibitor That Affords Robust CNS A beta Reduction without Cardiovascular Liabilities.
Acs Med.Chem.Lett., 6:210-215, 2015

PubMed Abstract: BACE1 inhibition to prevent Aβ peptide formation is considered to be a potential route to a disease-modifying treatment for Alzheimer's disease. Previous efforts in our laboratory using a combined structure- and property-based approach have resulted in the identification of aminooxazoline xanthenes as potent BACE1 inhibitors. Herein, we report further optimization leading to the discovery of inhibitor 15 as an orally available and highly efficacious BACE1 inhibitor that robustly reduces CSF and brain Aβ levels in both rats and nonhuman primates. In addition, compound 15 exhibited low activity on the hERG ion channel and was well tolerated in an integrated cardiovascular safety model.

PubMed: 25699151
DOI: 10.1021/ml500458t

実験手法

X-RAY DIFFRACTION (1.85 Å)