4b1d

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[[Image:4b1d.png|left|200px]]
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==New Aminoimidazoles as BACE-1 Inhibitors: From Rational Design to Ab- lowering in Brain==
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<StructureSection load='4b1d' size='340' side='right' caption='[[4b1d]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4b1d]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B1D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B1D FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6TG:(2S)-2-(4-METHOXY-3,5-DIMETHYLPHENYL)-5-METHYL-2-(3-PYRIMIDIN-5-YLPHENYL)-2H-IMIDAZOL-4-AMINE'>6TG</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1fkn|1fkn]], [[1m4h|1m4h]], [[1py1|1py1]], [[1sgz|1sgz]], [[1tqf|1tqf]], [[1ujj|1ujj]], [[1ujk|1ujk]], [[1w50|1w50]], [[1w51|1w51]], [[1xn2|1xn2]], [[1xn3|1xn3]], [[1xs7|1xs7]], [[1ym2|1ym2]], [[1ym4|1ym4]], [[2b8l|2b8l]], [[2b8v|2b8v]], [[2fdp|2fdp]], [[2va5|2va5]], [[2va6|2va6]], [[2va7|2va7]], [[2vie|2vie]], [[2vij|2vij]], [[2viy|2viy]], [[2viz|2viz]], [[2vj6|2vj6]], [[2vj7|2vj7]], [[2vj9|2vj9]], [[2vkm|2vkm]], [[2vnm|2vnm]], [[2vnn|2vnn]], [[2wez|2wez]], [[2wf0|2wf0]], [[2wf1|2wf1]], [[2wf2|2wf2]], [[2wf3|2wf3]], [[2wf4|2wf4]], [[2wjo|2wjo]], [[2xfi|2xfi]], [[2xfj|2xfj]], [[2xfk|2xfk]], [[4acu|4acu]], [[4acx|4acx]], [[4azy|4azy]], [[4b00|4b00]], [[4b05|4b05]], [[4b0q|4b0q]], [[4b1c|4b1c]], [[4b1e|4b1e]]</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4b1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b1d OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4b1d RCSB], [http://www.ebi.ac.uk/pdbsum/4b1d PDBsum]</span></td></tr>
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</table>
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== Function ==
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[[http://www.uniprot.org/uniprot/BACE1_HUMAN 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.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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{{STRUCTURE_4b1d| PDB=4b1d | SCENE= }}
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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<ref>PMID:23017051</ref>
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===New Aminoimidazoles as BACE-1 Inhibitors: From Rational Design to Ab- lowering in Brain===
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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{{ABSTRACT_PUBMED_23017051}}
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==See Also==
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*[[Beta secretase|Beta secretase]]
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==About this Structure==
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== References ==
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[[4b1d]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4B1D OCA].
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Memapsin 2]]
[[Category: Memapsin 2]]
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[[Category: Berg, S.]]
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[[Category: Berg, S]]
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[[Category: Blid, J.]]
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[[Category: Blid, J]]
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[[Category: Eketjall, S.]]
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[[Category: Eketjall, S]]
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[[Category: Falting, J.]]
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[[Category: Falting, J]]
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[[Category: Ginman, T.]]
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[[Category: Ginman, T]]
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[[Category: Gravenfors, Y.]]
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[[Category: Gravenfors, Y]]
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[[Category: Janson, J.]]
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[[Category: Janson, J]]
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[[Category: Jeppsson, F.]]
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[[Category: Jeppsson, F]]
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[[Category: Johansson, P.]]
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[[Category: Johansson, P]]
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[[Category: Karlstrom, S.]]
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[[Category: Karlstrom, S]]
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[[Category: Kieseritzky, F.]]
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[[Category: Kieseritzky, F]]
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[[Category: Kihlstrom, J.]]
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[[Category: Kihlstrom, J]]
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[[Category: Kolmodin, K.]]
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[[Category: Kolmodin, K]]
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[[Category: Lindstrom, J.]]
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[[Category: Lindstrom, J]]
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[[Category: Olsson, L.]]
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[[Category: Olsson, L]]
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[[Category: Rahm, F.]]
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[[Category: Rahm, F]]
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[[Category: Slivo, C.]]
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[[Category: Slivo, C]]
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[[Category: Stromberg, K.]]
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[[Category: Stromberg, K]]
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[[Category: Swahn, B.]]
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[[Category: Swahn, B]]
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[[Category: Viklund, J.]]
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[[Category: Viklund, J]]
[[Category: Hydrolase]]
[[Category: Hydrolase]]
[[Category: Inhibitor]]
[[Category: Inhibitor]]
[[Category: Lead generation]]
[[Category: Lead generation]]
[[Category: Structure-based drug design]]
[[Category: Structure-based drug design]]

Revision as of 20:27, 25 December 2014

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

4b1d, resolution 1.95Å

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