View source for 4azy

==Design and Synthesis of BACE1 Inhibitors with In Vivo Brain Reduction of beta-Amyloid Peptides (COMPOUND 10)==
<StructureSection load='4azy' size='340' side='right' caption='[[4azy]], [[Resolution|resolution]] 1.79&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4azy]] 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=4AZY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4AZY FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7F3:(1S)-4-FLUORO-1-(4-FLUORO-3-PYRIMIDIN-5-YLPHENYL)-1-[2-(TRIFLUOROMETHYL)PYRIDIN-4-YL]-1H-ISOINDOL-3-AMINE'>7F3</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>
<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]], [[4b00|4b00]], [[4b05|4b05]]</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=4azy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4azy OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4azy RCSB], [http://www.ebi.ac.uk/pdbsum/4azy PDBsum]</span></td></tr>
</table>
== Function ==
[[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>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The evaluation of a series of aminoisoindoles as beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Abeta40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 muM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of beta-amyloid peptides in mouse brain following oral dosing.

Design and Synthesis of beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1) Inhibitors with in Vivo Brain Reduction of beta-Amyloid Peptides.,Swahn BM, Kolmodin K, Karlstrom S, von Berg S, Soderman P, Holenz J, Berg S, Lindstrom J, Sundstrom M, Turek D, Kihlstrom J, Slivo C, Andersson L, Pyring D, Rotticci D, Ohberg L, Kers A, Bogar K, von Kieseritzky F, Bergh M, Olsson LL, Janson J, Eketjall S, Georgievska B, Jeppsson F, Falting J J Med Chem. 2012 Sep 17. PMID:22924815<ref>PMID:22924815</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>

==See Also==
*[[Beta secretase|Beta secretase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Memapsin 2]]
[[Category: Andersson, L]]
[[Category: Berg, S]]
[[Category: Bergh, M]]
[[Category: Bogar, K]]
[[Category: Eketjall, S]]
[[Category: Falting, J]]
[[Category: Georgievska, B]]
[[Category: Holenz, J]]
[[Category: Janson, J]]
[[Category: Jeppsson, F]]
[[Category: Karlstrom, S]]
[[Category: Kers, A]]
[[Category: Kihlstrom, J]]
[[Category: Kolmodin, K]]
[[Category: Lindstrom, J]]
[[Category: Ohberg, L]]
[[Category: Olsson, L L]]
[[Category: Pyring, D]]
[[Category: Slivo, C]]
[[Category: Soderman, P]]
[[Category: Sundstrom, M]]
[[Category: Swahn, B M]]
[[Category: Turek, D]]
[[Category: Vonberg, S]]
[[Category: Alzheimer's disease]]
[[Category: Aminoisoindole]]
[[Category: Hydrolase]]