4b70 | pdb_00004b70

Aminoimidazoles as BACE-1 Inhibitors: From De Novo Design to Ab- lowering in Brain

spinqualitylabelsall models 4b70, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4b70 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: WM9 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, 4b1e, 4b72, 4b77, 4b78 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 By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 muM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds. Core Refinement toward Permeable beta-Secretase (BACE-1) Inhibitors with Low hERG Activity.,Ginman T, Viklund J, Malmstrom J, Blid J, Emond R, Forsblom R, Johansson A, Kers A, Lake F, Sehgelmeble F, Sterky KJ, Bergh M, Lindgren A, Johansson P, Jeppsson F, Falting J, Gravenfors Y, Rahm F J Med Chem. 2013 Jun 13;56(11):4181-205. doi: 10.1021/jm3011349. Epub 2013 May, 20. PMID:23126626 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase

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