4b70: Difference between revisions
Jump to navigation
Jump to search
No edit summary |
No edit summary |
||
| (4 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
== | ==Aminoimidazoles as BACE-1 Inhibitors: From De Novo Design to Ab- lowering in Brain== | ||
[[http://www.uniprot.org/uniprot/BACE1_HUMAN BACE1_HUMAN | <StructureSection load='4b70' size='340' side='right'caption='[[4b70]], [[Resolution|resolution]] 1.60Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4b70]] 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=4B70 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B70 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]] 1.6Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=WM9:(2S)-2-[3-(3-CHLOROPHENYL)PHENYL]-2-METHYL-5,6-DIHYDRO-1,3-OXAZIN-4-AMINE'>WM9</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=4b70 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b70 OCA], [https://pdbe.org/4b70 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b70 RCSB], [https://www.ebi.ac.uk/pdbsum/4b70 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b70 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 == | |||
By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 muM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds. | |||
Core Refinement toward Permeable beta-Secretase (BACE-1) Inhibitors with Low hERG Activity.,Ginman T, Viklund J, Malmstrom J, Blid J, Emond R, Forsblom R, Johansson A, Kers A, Lake F, Sehgelmeble F, Sterky KJ, Bergh M, Lindgren A, Johansson P, Jeppsson F, Falting J, Gravenfors Y, Rahm F J Med Chem. 2013 Jun 13;56(11):4181-205. doi: 10.1021/jm3011349. Epub 2013 May, 20. PMID:23126626<ref>PMID:23126626</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
< | </div> | ||
<div class="pdbe-citations 4b70" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Berg | [[Category: Berg S]] | ||
[[Category: Blid | [[Category: Blid J]] | ||
[[Category: Eketjall | [[Category: Eketjall S]] | ||
[[Category: Falting | [[Category: Falting J]] | ||
[[Category: Ginman | [[Category: Ginman T]] | ||
[[Category: Gravenfors | [[Category: Gravenfors Y]] | ||
[[Category: Janson | [[Category: Janson J]] | ||
[[Category: Jeppsson | [[Category: Jeppsson F]] | ||
[[Category: Johansson | [[Category: Johansson P]] | ||
[[Category: Karlstrom | [[Category: Karlstrom S]] | ||
[[Category: Kieseritzky | [[Category: Kieseritzky F]] | ||
[[Category: Kihlstrom | [[Category: Kihlstrom J]] | ||
[[Category: Kolmodin | [[Category: Kolmodin K]] | ||
[[Category: Lindstrom | [[Category: Lindstrom J]] | ||
[[Category: Olsson | [[Category: Olsson L]] | ||
[[Category: Rahm | [[Category: Rahm F]] | ||
[[Category: Slivo | [[Category: Slivo C]] | ||
[[Category: Stromberg | [[Category: Stromberg K]] | ||
[[Category: Swahn | [[Category: Swahn B]] | ||
[[Category: Viklund | [[Category: Viklund J]] | ||
Latest revision as of 11:19, 23 October 2024
Aminoimidazoles as BACE-1 Inhibitors: From De Novo Design to Ab- lowering in BrainAminoimidazoles as BACE-1 Inhibitors: From De Novo Design to Ab- lowering in Brain
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 PubMedBy use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 muM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds. Core Refinement toward Permeable beta-Secretase (BACE-1) Inhibitors with Low hERG Activity.,Ginman T, Viklund J, Malmstrom J, Blid J, Emond R, Forsblom R, Johansson A, Kers A, Lake F, Sehgelmeble F, Sterky KJ, Bergh M, Lindgren A, Johansson P, Jeppsson F, Falting J, Gravenfors Y, Rahm F J Med Chem. 2013 Jun 13;56(11):4181-205. doi: 10.1021/jm3011349. Epub 2013 May, 20. PMID:23126626[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||