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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 [ | <table><tr><td colspan='2'>[[4azy]] 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=4AZY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/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='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.79Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4azy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4azy OCA], [https://pdbe.org/4azy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4azy RCSB], [https://www.ebi.ac.uk/pdbsum/4azy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4azy ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 18: | Line 18: | ||
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== | ||
*[[Beta secretase|Beta secretase]] | *[[Beta secretase 3D structures|Beta secretase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 26: | Line 27: | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Andersson | [[Category: Andersson L]] | ||
[[Category: Berg | [[Category: Berg S]] | ||
[[Category: Bergh | [[Category: Bergh M]] | ||
[[Category: Bogar | [[Category: Bogar K]] | ||
[[Category: Eketjall | [[Category: Eketjall S]] | ||
[[Category: Falting | [[Category: Falting J]] | ||
[[Category: Georgievska | [[Category: Georgievska B]] | ||
[[Category: Holenz | [[Category: Holenz J]] | ||
[[Category: Janson | [[Category: Janson J]] | ||
[[Category: Jeppsson | [[Category: Jeppsson F]] | ||
[[Category: Karlstrom | [[Category: Karlstrom S]] | ||
[[Category: Kers | [[Category: Kers A]] | ||
[[Category: Kihlstrom | [[Category: Kihlstrom J]] | ||
[[Category: Kolmodin | [[Category: Kolmodin K]] | ||
[[Category: Lindstrom | [[Category: Lindstrom J]] | ||
[[Category: Ohberg | [[Category: Ohberg L]] | ||
[[Category: Olsson | [[Category: Olsson LL]] | ||
[[Category: Pyring | [[Category: Pyring D]] | ||
[[Category: Slivo | [[Category: Slivo C]] | ||
[[Category: Soderman | [[Category: Soderman P]] | ||
[[Category: Sundstrom | [[Category: Sundstrom M]] | ||
[[Category: Swahn | [[Category: Swahn BM]] | ||
[[Category: Turek | [[Category: Turek D]] | ||
[[Category: | [[Category: Von Berg S]] | ||
Latest revision as of 14:39, 20 December 2023
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
FunctionBACE1_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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