4XKX

Crystal structure of BACE1 in complex with 2-aminooxazoline 3-azaxanthene inhibitor 28

Summary for 4XKX

• Entry DOI: 10.2210/pdb4xkx/pdb
• Related: 4RCD 4RCE 4RCF 4WTU
• Descriptor: Beta-secretase 1, IODIDE ION, (5S)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)spiro[chromeno[2,3-c]pyridine-5,4'-[1,3]oxazol]-2'-amine, ... (5 entities in total)
• Functional Keywords: aspartic protease, 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: 46957.65

Authors

Whittington, D.A.,Long, A.M. (deposition date: 2015-01-12, release date: 2015-02-04, Last modification date: 2024-11-20)

Primary citation

Chen, J.J.,Liu, Q.,Yuan, C.,Gore, V.,Lopez, P.,Ma, V.,Amegadzie, A.,Qian, W.,Judd, T.C.,Minatti, A.E.,Brown, J.,Cheng, Y.,Xue, M.,Zhong, W.,Dineen, T.A.,Epstein, O.,Human, J.,Kreiman, C.,Marx, I.,Weiss, M.M.,Hitchcock, S.A.,Powers, T.S.,Chen, K.,Wen, P.H.,Whittington, D.A.,Cheng, A.C.,Bartberger, M.D.,Hickman, D.,Werner, J.A.,Vargas, H.M.,Everds, N.E.,Vonderfecht, S.L.,Dunn, R.T.,Wood, S.,Fremeau, R.T.,White, R.D.,Patel, V.F.
Development of 2-aminooxazoline 3-azaxanthenes as orally efficacious beta-secretase inhibitors for the potential treatment of Alzheimer's disease.
Bioorg.Med.Chem.Lett., 25:767-774, 2015

PubMed Abstract: The β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) is one of the most hotly pursued targets for the treatment of Alzheimer's disease. We used a structure- and property-based drug design approach to identify 2-aminooxazoline 3-azaxanthenes as potent BACE1 inhibitors which significantly reduced CSF and brain Aβ levels in a rat pharmacodynamic model. Compared to the initial lead 2, compound 28 exhibited reduced potential for QTc prolongation in a non-human primate cardiovascular safety model.

PubMed: 25613679
DOI: 10.1016/j.bmcl.2014.12.092

Experimental method

X-RAY DIFFRACTION (1.8 Å)