4acx

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

spinqualitylabelsall models 4acx, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4acx 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: ACT, S8Z 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 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 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 300mumol/kg (R)-25 and efflux inhibitor GF120918 the brain Abeta40 level was reduced by 17% and the plasma Abeta40 level by 76%. Aminoimidazoles as BACE-1 inhibitors: The challenge to achieve in vivo brain efficacy.,Swahn BM, Holenz J, Kihlstrom J, Kolmodin K, Lindstrom J, Plobeck N, Rotticci D, Sehgelmeble F, Sundstrom M, Berg S, Falting J, Georgievska B, Gustavsson S, Neelissen J, Ek M, Olsson LL, Berg S Bioorg Med Chem Lett. 2012 Mar 1;22(5):1854-9. Epub 2012 Jan 28. PMID:22325942 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

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