4B1E

New Aminoimidazoles as BACE-1 Inhibitors: From Rational Design to Ab- lowering in Brain

Summary for 4B1E

• Entry DOI: 10.2210/pdb4b1e/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 4ACX 4AZY 4B00 4B05 4B0Q 4B1C 4B1D
• Descriptor: BETA-SECRETASE 1, (2R)-2-methyl-5-phenyl-2-(3-pyridin-3-ylphenyl)-2,3-dihydro-1H-imidazol-4-amine (3 entities in total)
• Functional Keywords: hydrolase, structure-based drug design
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 43527.11

Authors

Rahm, F.,Blid, J.,Ginman, T.,Karlstrom, S.,Kihlstrom, J.,Kolmodin, K.,Lindstrom, J.,von Berg, S.,von Kieseritzky, F.,Slivo, C.,Swahn, B.,Viklund, J.,Olsson, L.,Johansson, P.,Eketjall, S.,Falting, J.,Jeppsson, F.,Stromberg, K.,Janson, J.,Gravenfors, Y. (deposition date: 2012-07-10, release date: 2012-10-10, Last modification date: 2018-02-14)

Primary citation

Gravenfors, Y.,Viklund, J.,Blid, J.,Ginman, T.,Karlstrom, S.,Kihlstrom, J.,Kolmodin, K.,Lindstrom, J.,von Berg, S.,von Kieseritzky, F.,Bogar, K.,Slivo, C.,Swahn, B.M.,Olsson, L.L.,Johansson, P.,Eketjall, S.,Falting, J.,Jeppsson, F.,Stromberg, K.,Janson, J.,Rahm, F.
New aminoimidazoles as beta-secretase (BACE-1) inhibitors showing amyloid-beta (A beta ) lowering in brain.
J. Med. Chem., 55:9297-9311, 2012

PubMed Abstract: Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Aβ40 and Aβ42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aβ was 40-50%, 1.5 h after oral dosing (100 μmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.

PubMed: 23017051
DOI: 10.1021/jm300991n

Experimental method

X-RAY DIFFRACTION (1.95 Å)