4ACX

Aminoimidazoles as BACE-1 Inhibitors. X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 23

Summary for 4ACX

• Entry DOI: 10.2210/pdb4acx/pdb
• Related: 1FKN 1M4H 1PY1 1SGZ 1TQF 1UJJ 1UJK 1W50 1W51 1XN2 1XN3 1XS7 1YM2 1YM4 2B8L 2B8V 2FDP 2VA5 2VA6 2VA7 2VIE 2VIJ 2VIY 2VIZ 2VJ6 2VJ7 2VJ9 2VKM 2VNM 2VNN 2WEZ 2WF0 2WF1 2WF2 2WF3 2WF4 2WJO 2XFI 2XFJ 2XFK 4ACU
• Descriptor: BETA-SECRETASE 1, ACETATE ION, (8R)-8-[4-(DIFLUOROMETHOXY)PHENYL]-3,3-DIFLUORO-8-[3-(3-METHOXYPROP-1-YN-1-YL)PHENYL]-2,3,4,8-TETRAHYDROIMIDAZO[1,5-A]PYRIMIDIN-6-AMINE, ... (4 entities in total)
• Functional Keywords: hydrolase, alzheimer's disease
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 46341.91

Authors

Swahn, B.,Holenz, J.,Kihlstrom, J.,Kolmodin, K.,Lindstrom, J.,Plobeck, N.,Rotticci, D.,Sehgelmeble, F.,Sundstrom, M.,von Berg, S.,Falting, J.,Georgievska, B.,Gustavsson, S.,Neelissen, J.,Ek, M.,Olsson, L.L.,Berg, S. (deposition date: 2011-12-20, release date: 2012-02-29, Last modification date: 2024-10-23)

Primary citation

Swahn, B.M.,Holenz, J.,Kihlstrom, J.,Kolmodin, K.,Lindstrom, J.,Plobeck, N.,Rotticci, D.,Sehgelmeble, F.,Sundstrom, M.,Berg, S.v.,Falting, J.,Georgievska, B.,Gustavsson, S.,Neelissen, J.,Ek, M.,Olsson, L.L.,Berg, S.
Aminoimidazoles as BACE-1 inhibitors: the challenge to achieve in vivo brain efficacy.
Bioorg. Med. Chem. Lett., 22:1854-1859, 2012

PubMed Abstract: The evaluation of a series of bicyclic aminoimidazoles as potent BACE-1 inhibitors is described. The crystal structures of compounds 14 and 23 in complex with BACE-1 reveal hydrogen bond interactions with the protein important for achieving potent inhibition. The optimization of permeability and efflux properties of the compounds is discussed as well as the importance of these properties for attaining in vivo brain efficacy. Compound (R)-25 was selected for evaluation in vivo in wild type mice and 1.5h after oral co-administration of 300μmol/kg (R)-25 and efflux inhibitor GF120918 the brain Aβ40 level was reduced by 17% and the plasma Aβ40 level by 76%.

PubMed: 22325942
DOI: 10.1016/j.bmcl.2012.01.079

Experimental method

X-RAY DIFFRACTION (2 Å)