3U6A

Rational Design and Synthesis of Aminopiperazinones as Beta Secretase (BACE) Inhibitors

Summary for 3U6A

• Entry DOI: 10.2210/pdb3u6a/pdb
• Descriptor: Beta-secretase 1, N-{3-[(2R)-6-amino-2,4-dimethyl-3-oxo-2,3,4,5-tetrahydropyrazin-2-yl]phenyl}-5-chloropyridine-2-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: beta-site app cleaving enzyme 1, 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: 132131.68

Authors

Spurlino, J.C.,Alexander, R.S. (deposition date: 2011-10-12, release date: 2011-11-09, Last modification date: 2024-11-06)

Primary citation

Tresadern, G.,Delgado, F.,Delgado, O.,Gijsen, H.,Macdonald, G.J.,Moechars, D.,Rombouts, F.,Alexander, R.,Spurlino, J.,Van Gool, M.,Vega, J.A.,Trabanco, A.A.
Rational design and synthesis of aminopiperazinones as beta-secretase (BACE) inhibitors.
Bioorg.Med.Chem.Lett., 21:7255-7260, 2011

PubMed Abstract: Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.

PubMed: 22071305
DOI: 10.1016/j.bmcl.2011.10.050

Experimental method

X-RAY DIFFRACTION (2.199 Å)