4DI2

Crystal structure of BACE1 in complex with hydroxyethylamine inhibitor 37

Summary for 4DI2

• Entry DOI: 10.2210/pdb4di2/pdb
• Descriptor: 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)
• Functional Keywords: memapsin-2, alzheimer's disease, protease, beta-site amyloid precursor protein cleaving enzyme 1, app, 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: 3
• Total formula weight: 139706.18

Authors

Whittington, D.A.,Long, A.M. (deposition date: 2012-01-30, release date: 2012-10-10, Last modification date: 2024-11-27)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2 Å)