4RCE

Crystal structure of BACE1 in complex with aminooxazoline xanthene inhibitor 2

4RCE の概要

• エントリーDOI: 10.2210/pdb4rce/pdb
• 関連するPDBエントリー: 4RCD 4RCF
• 分子名称: Beta-secretase 1, (4S)-2'-(2,2-dimethylpropoxy)-7'-(pyrimidin-5-yl)spiro[1,3-oxazole-4,9'-xanthen]-2-amine, IODIDE ION, ... (4 entities in total)
• 機能のキーワード: aspartic protease, alzheimer's disease, app, amyloid precursor protein, brain, 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: 46619.63

構造登録者

Whittington, D.A.,Long, A.M. (登録日: 2014-09-15, 公開日: 2014-12-24, 最終更新日: 2024-11-06)

主引用文献

Epstein, O.,Bryan, M.C.,Cheng, A.C.,Derakhchan, K.,Dineen, T.A.,Hickman, D.,Hua, Z.,Human, J.B.,Kreiman, C.,Marx, I.E.,Weiss, M.M.,Wahl, R.C.,Wen, P.H.,Whittington, D.A.,Wood, S.,Zheng, X.M.,Fremeau, R.T.,White, R.D.,Patel, V.F.
Lead Optimization and Modulation of hERG Activity in a Series of Aminooxazoline Xanthene beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors.
J.Med.Chem., 57:9796-9810, 2014

PubMed Abstract: The optimization of a series of aminooxazoline xanthene inhibitors of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aβ lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aβ reduction in a rat pharmacodynamic model (78% Aβ reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

PubMed: 25389560
DOI: 10.1021/jm501266w

実験手法

X-RAY DIFFRACTION (2.4 Å)