4b1c

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

spinqualitylabelsall models 4b1c, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4b1c is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 1B1, DMS 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, 4b1d, 4b1e Activity: Memapsin 2, with EC number 3.4.23.46 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. Publication Abstract from PubMed 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 Abeta40 and Abeta42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Abeta was 40-50%, 1.5 h after oral dosing (100 mumol/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. New Aminoimidazoles as beta-Secretase (BACE-1) Inhibitors Showing Amyloid-beta (Abeta) Lowering in Brain.,Gravenfors Y, Viklund J, Blid J, Ginman T, Karlstrom S, Kihlstrom J, Kolmodin K, Lindstrom J, von Berg S, von Kieseritzky F, Slivo C, Swahn BM, Olsson LL, Johansson P, Eketjall S, Falting J, Jeppsson F, Stromberg K, Janson J, Rahm F J Med Chem. 2012 Oct 3. PMID:23017051 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

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