4r5n
From Proteopedia
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| - | ''' | + | ==8-Tetrahydropyran-2-yl chromans: highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors== |
| + | <StructureSection load='4r5n' size='340' side='right' caption='[[4r5n]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4r5n]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R5N OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R5N FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3J9:(4R,4AS,10AR)-8-(2-FLUOROPYRIDIN-3-YL)-4A-METHYL-3,4,4A,10A-TETRAHYDRO-2H-SPIRO[1,3-OXAZOLE-4,10-PYRANO[3,2-B]CHROMEN]-2-AMINE'>3J9</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4n00|4n00]], [[4rrn|4rrn]], [[4rro|4rro]], [[4rrs|4rrs]]</td></tr> | ||
| + | <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> | ||
| + | <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=4r5n FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r5n OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r5n RCSB], [http://www.ebi.ac.uk/pdbsum/4r5n PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | A series of 2,3,4,4a,10,10a-hexahydropyrano[3,2-b]chromene analogs was developed that demonstrated high selectivity (>2000-fold) for BACE1 vs Cathepsin D (CatD). Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Guided by structure based design, changes to P2' and P3 moieties were explored. A conformationally restricted P2' methyl group provided inhibitors with excellent cell potency (37-137 nM) and selectivity (435 to >2000-fold) for BACE1 vs CatD. These efforts lead to compound 59, which demonstrated a 69% reduction in rat CSF Abeta1-40 at 60 mg/kg (PO). | ||
| - | + | 8-Tetrahydropyran-2-yl Chromans: Highly Selective Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors.,Thomas AA, Hunt KW, Newhouse B, Watts RJ, Liu X, Vigers G, Smith D, Rhodes SP, Brown KD, Otten JN, Burkard M, Cox AA, Geck Do MK, Dutcher D, Rana S, DeLisle RK, Regal K, Wright AD, Groneberg R, Liao J, Scearce-Levie K, Siu M, Purkey HE, Lyssikatos JP J Med Chem. 2014 Nov 26. PMID:25411915<ref>PMID:25411915</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Memapsin 2]] | ||
| + | [[Category: Smith, D]] | ||
| + | [[Category: Vigers, G P.A]] | ||
| + | [[Category: Aspartyl protease]] | ||
| + | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 09:23, 3 December 2014
8-Tetrahydropyran-2-yl chromans: highly selective beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors
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