4azy: Difference between revisions
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==Design and Synthesis of BACE1 Inhibitors with In Vivo Brain Reduction of beta-Amyloid Peptides (COMPOUND 10)== | ==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]] 1.79Å' scene=''> | <StructureSection load='4azy' size='340' side='right' caption='[[4azy]], [[Resolution|resolution]] 1.79Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4azy]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[4azy]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. 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> | </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='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='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> | <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://pdbe.org/4azy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4azy RCSB], [http://www.ebi.ac.uk/pdbsum/4azy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4azy ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4azy" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Human]] | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Andersson, L]] | [[Category: Andersson, L]] | ||
Revision as of 06:07, 5 August 2016
Design and Synthesis of BACE1 Inhibitors with In Vivo Brain Reduction of beta-Amyloid Peptides (COMPOUND 10)Design and Synthesis of BACE1 Inhibitors with In Vivo Brain Reduction of beta-Amyloid Peptides (COMPOUND 10)
Structural highlights
Function[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.[1] [2] Publication Abstract from PubMedThe 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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