5clm

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'''Unreleased structure'''
 
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The entry 5clm is ON HOLD
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==1,4-Oxazine BACE1 inhibitors==
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<StructureSection load='5clm' size='340' side='right'caption='[[5clm]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[5clm]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CLM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CLM FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.61&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=52K:N-{3-[(3R)-5-AMINO-3-METHYL-3,6-DIHYDRO-2H-1,4-OXAZIN-3-YL]PHENYL}-5-CHLOROPYRIDINE-2-CARBOXAMIDE'>52K</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5clm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5clm OCA], [https://pdbe.org/5clm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5clm RCSB], [https://www.ebi.ac.uk/pdbsum/5clm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5clm ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://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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1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa whilst optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active and which demonstrated robust lowering of Abeta levels in vivo in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE inhibitors for the treatment of Alzheimer's Disease.
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Authors: Rombouts, F., Tresadern, G., Delgado, O., Martinez Lamenca, C., Van Gool, M., Garcia-Molina, A., Alonso De Diego, S., Oehlrich, D., Prokopcova, H., Alonso, J.M., Austin, N., Borghys, H., Van Brandt, S., Surkyn, M., De Cleyn, M., Vos, A., Alexander, R., MacDonald, G., Moechars, D., Trabanco, A., Gijsen, H.
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1,4-Oxazine beta-secretase (BACE1) inhibitors: from hit generation to orally bioavailable brain penetrant leads.,Rombouts FJ, Tresadern G, Delgado O, Martinez Lamenca C, Van Gool M, Garcia-Molina A, Alonso De Diego SA, Oehlrich D, Prokopcova H, Alonso JM, Austin N, Borghys H, Van Brandt S, Surkyn M, De Cleyn M, Vos A, Alexander R, Macdonald GJ, Moechars D, Gijsen HJ, Trabanco AA J Med Chem. 2015 Sep 17. PMID:26378740<ref>PMID:26378740</ref>
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Description: 1,4-Oxazine BACE1 inhibitors
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Oehlrich, D]]
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<div class="pdbe-citations 5clm" style="background-color:#fffaf0;"></div>
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[[Category: Tresadern, G]]
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[[Category: Moechars, D]]
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==See Also==
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[[Category: Delgado, O]]
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*[[Beta secretase 3D structures|Beta secretase 3D structures]]
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[[Category: Alexander, R]]
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== References ==
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[[Category: De Cleyn, M]]
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<references/>
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[[Category: Surkyn, M]]
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__TOC__
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[[Category: Prokopcova, H]]
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</StructureSection>
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[[Category: Garcia-Molina, A]]
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[[Category: Homo sapiens]]
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[[Category: Van Gool, M]]
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[[Category: Large Structures]]
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[[Category: Martinez Lamenca, C]]
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[[Category: Alexander R]]
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[[Category: Rombouts, F]]
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[[Category: Alonso De Diego S]]
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[[Category: Alonso, J.M]]
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[[Category: Alonso JM]]
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[[Category: Austin, N]]
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[[Category: Austin N]]
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[[Category: Alonso De Diego, S]]
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[[Category: Borghys H]]
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[[Category: Trabanco, A]]
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[[Category: De Cleyn M]]
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[[Category: Borghys, H]]
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[[Category: Delgado O]]
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[[Category: Van Brandt, S]]
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[[Category: Garcia-Molina A]]
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[[Category: Gijsen, H]]
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[[Category: Gijsen H]]
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[[Category: Vos, A]]
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[[Category: MacDonald G]]
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[[Category: Macdonald, G]]
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[[Category: Martinez Lamenca C]]
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[[Category: Moechars D]]
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[[Category: Oehlrich D]]
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[[Category: Prokopcova H]]
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[[Category: Rombouts F]]
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[[Category: Surkyn M]]
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[[Category: Trabanco A]]
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[[Category: Tresadern G]]
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[[Category: Van Brandt S]]
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[[Category: Van Gool M]]
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[[Category: Vos A]]

Current revision

1,4-Oxazine BACE1 inhibitors

PDB ID 5clm

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