4WTU

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

Summary for 4WTU

• Entry DOI: 10.2210/pdb4wtu/pdb
• Related: 4RCD 4RCE 4RCF
• Descriptor: Beta-secretase 1, IODIDE ION, GLYCEROL, ... (5 entities in total)
• Functional Keywords: aspartic protease, amyloid precursor protein, alzheimer's disease, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 46962.67

Authors

Whittington, D.A.,Long, A.M. (deposition date: 2014-10-30, release date: 2015-03-04, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.85 Å)