View source for 5ygy


==Crystal Structure of BACE1 in complex with (S)-N-(3-(2-amino-6-(fluoromethyl)-4 -methyl-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide==
<StructureSection load='5ygy' size='340' side='right'caption='[[5ygy]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ygy]] 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=5YGY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5YGY FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0B6:~{N}-[3-[(4~{S})-2-azanyl-6-(fluoranylmethyl)-4-methyl-1,3-oxazin-4-yl]-4-fluoranyl-phenyl]-5-cyano-pyridine-2-carboxamide'>0B6</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5ygy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ygy OCA], [https://pdbe.org/5ygy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ygy RCSB], [https://www.ebi.ac.uk/pdbsum/5ygy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ygy ProSAT]</span></td></tr>
</table>
== Function ==
[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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Accumulation of Abeta peptides is a hallmark of Alzheimer's disease (AD) and is considered a causal factor in the pathogenesis of AD. beta-Secretase (BACE1) is a key enzyme responsible for producing Abeta peptides, and thus agents that inhibit BACE1 should be beneficial for disease-modifying treatment of AD. Here we describe the discovery and optimization of novel oxazine-based BACE1 inhibitors by lowering amidine basicity with the incorporation of a double bond to improve brain penetration. Starting from a 1,3-dihydrooxazine lead 6 identified by a hit-to-lead SAR following HTS, we adopted a p Ka lowering strategy to reduce the P-gp efflux and the high hERG potential leading to the discovery of 15 that produced significant Abeta reduction with long duration in pharmacodynamic models and exhibited wide safety margins in cardiovascular safety models. This compound improved the brain-to-plasma ratio relative to 6 by reducing P-gp recognition, which was demonstrated by a P-gp knockout mouse model.

Rational Design of Novel 1,3-Oxazine Based beta-Secretase (BACE1) Inhibitors: Incorporation of a Double Bond To Reduce P-gp Efflux Leading to Robust Abeta Reduction in the Brain.,Fuchino K, Mitsuoka Y, Masui M, Kurose N, Yoshida S, Komano K, Yamamoto T, Ogawa M, Unemura C, Hosono M, Ito H, Sakaguchi G, Ando S, Ohnishi S, Kido Y, Fukushima T, Miyajima H, Hiroyama S, Koyabu K, Dhuyvetter D, Borghys H, Gijsen HJM, Yamano Y, Iso Y, Kusakabe KI J Med Chem. 2018 May 23. doi: 10.1021/acs.jmedchem.8b00002. PMID:29733614<ref>PMID:29733614</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5ygy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ando S]]
[[Category: Borghys H]]
[[Category: Dhuyvetter D]]
[[Category: Fuchino K]]
[[Category: Fukushima T]]
[[Category: Gijsen H]]
[[Category: Hiroyama S]]
[[Category: Hosono M]]
[[Category: Iso Y]]
[[Category: Ito H]]
[[Category: Kido Y]]
[[Category: Komano K]]
[[Category: Koyabu K]]
[[Category: Kurose N]]
[[Category: Kusakabe K]]
[[Category: Masui M]]
[[Category: Mitsuoka Y]]
[[Category: Miyajima H]]
[[Category: Ogawa M]]
[[Category: Ohnishi S]]
[[Category: Sakaguchi G]]
[[Category: Unemura C]]
[[Category: Yamamoto T]]
[[Category: Yamano Y]]
[[Category: Yoshida S]]