4fm7: Difference between revisions
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==Crystal Structure of BACE with Compound 14g== | |||
=== | <StructureSection load='4fm7' size='340' side='right' caption='[[4fm7]], [[Resolution|resolution]] 1.56Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4fm7]] 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=4FM7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FM7 FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0UP:4-{[(5R,7S)-1-(3-FLUOROPHENYL)-3,7-DIMETHYL-2,2-DIOXIDO-2-THIA-1,3,8-TRIAZASPIRO[4.5]DEC-8-YL]METHYL}-2-(PROPAN-2-YLOXY)PHENOL'>0UP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4fm7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fm7 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4fm7 RCSB], [http://www.ebi.ac.uk/pdbsum/4fm7 PDBsum]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
beta-Secretase (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize CNS penetration by minimizing hydrogen bond donors (HBD) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogs and the in-silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central AbetaX-40 levels at a free drug exposure equivalent to the whole cell IC(50) (100 nM). Furthermore, studies in the P-gp knock-out mouse provided evidence that efflux transporters impacted the amount of Abeta lowering versus that observed in wild-type (WT) mouse at equivalent dose. | |||
Spirocyclic Sulfamides as BACE-1 Inhibitors for the Treatment of Alzheimer's Disease: Utilization of Structure Based Drug Design, WaterMap, and CNS Penetration Studies to Identify Centrally Efficacious Inhibitors.,Brodney MA, Barreiro G, Ogilvie K, Hajos-Korcsok E, Murray JC, Vajdos FF, Ambroise C, Christoffersen C, Fisher KE, Lanyon L, Liu J, Nolan CE, Withka JM, Borzilleri KA, Efremov IV, Oborski CE, Varghese AH, O'Neill BT J Med Chem. 2012 Sep 17. PMID:22984865<ref>PMID:22984865</ref> | |||
From MEDLINE®/PubMed®, 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: Homo sapiens]] | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Vajdos, F F | [[Category: Vajdos, F F]] | ||
[[Category: Varghese, A H | [[Category: Varghese, A H]] | ||
[[Category: Aspartyl protease]] | [[Category: Aspartyl protease]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 14:35, 21 December 2014
Crystal Structure of BACE with Compound 14gCrystal Structure of BACE with Compound 14g
Structural highlights
Publication Abstract from PubMedbeta-Secretase (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize CNS penetration by minimizing hydrogen bond donors (HBD) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogs and the in-silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central AbetaX-40 levels at a free drug exposure equivalent to the whole cell IC(50) (100 nM). Furthermore, studies in the P-gp knock-out mouse provided evidence that efflux transporters impacted the amount of Abeta lowering versus that observed in wild-type (WT) mouse at equivalent dose. Spirocyclic Sulfamides as BACE-1 Inhibitors for the Treatment of Alzheimer's Disease: Utilization of Structure Based Drug Design, WaterMap, and CNS Penetration Studies to Identify Centrally Efficacious Inhibitors.,Brodney MA, Barreiro G, Ogilvie K, Hajos-Korcsok E, Murray JC, Vajdos FF, Ambroise C, Christoffersen C, Fisher KE, Lanyon L, Liu J, Nolan CE, Withka JM, Borzilleri KA, Efremov IV, Oborski CE, Varghese AH, O'Neill BT J Med Chem. 2012 Sep 17. PMID:22984865[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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