4rcd

From Proteopedia

(Difference between revisions)

Revision as of 16:52, 21 January 2015

Crystal structure of BACE1 in complex with a 2-aminooxazoline 4-azaxanthene inhibitor

Structural highlights

4rcd is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	4rce, 4rcf
Activity:	Memapsin 2, with EC number 3.4.23.46
Resources:	FirstGlance, OCA, RCSB, PDBsum

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 PubMed

We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Abeta levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.

Inhibitors of beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[ 2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718).,Dineen TA, Chen K, Cheng AC, Derakhchan K, Epstein O, Esmay J, Hickman D, Kreiman CE, Marx IE, Wahl RC, Wen PH, Weiss MM, Whittington DA, Wood S, Fremeau RT Jr, White RD, Patel VF J Med Chem. 2014 Dec 11;57(23):9811-31. doi: 10.1021/jm5012676. Epub 2014 Nov 14. PMID:25363711^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
↑ Dineen TA, Chen K, Cheng AC, Derakhchan K, Epstein O, Esmay J, Hickman D, Kreiman CE, Marx IE, Wahl RC, Wen PH, Weiss MM, Whittington DA, Wood S, Fremeau RT Jr, White RD, Patel VF. Inhibitors of beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[ 2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718). J Med Chem. 2014 Dec 11;57(23):9811-31. doi: 10.1021/jm5012676. Epub 2014 Nov 14. PMID:25363711 doi:http://dx.doi.org/10.1021/jm5012676

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4rcd"

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
+==Crystal structure of BACE1 in complex with a 2-aminooxazoline 4-azaxanthene inhibitor==
+<StructureSection load='4rcd' size='340' side='right' caption='[[4rcd]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4rcd]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RCD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RCD FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3LL:(5S)-7-(2-FLUOROPYRIDIN-3-YL)-3-[(3-METHYLOXETAN-3-YL)ETHYNYL]SPIRO[CHROMENO[2,3-B]PYRIDINE-5,4-[1,3]OXAZOL]-2-AMINE'>3LL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4rce|4rce]], [[4rcf|4rcf]]</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=4rcd FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4rcd OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4rcd RCSB], [http://www.ebi.ac.uk/pdbsum/4rcd 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 ==
+We have previously shown that the aminooxazoline xanthene scaffold can generate potent and orally efficacious BACE1 inhibitors although certain of these compounds exhibited potential hERG liabilities. In this article, we describe 4-aza substitution on the xanthene core as a means to increase BACE1 potency while reducing hERG binding affinity. Further optimization of the P3 and P2' side chains resulted in the identification of 42 (AMG-8718), a compound with a balanced profile of BACE1 potency, hERG binding affinity, and Pgp recognition. This compound produced robust and sustained reductions of CSF and brain Abeta levels in a rat pharmacodynamic model and exhibited significantly reduced potential for QTc elongation in a cardiovascular safety model.
-The entry 4rcd is ON HOLD  until Paper Publication
+Inhibitors of beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE1): Identification of (S)-7-(2-Fluoropyridin-3-yl)-3-((3-methyloxetan-3-yl)ethynyl)-5'H-spiro[chromeno[ 2,3-b]pyridine-5,4'-oxazol]-2'-amine (AMG-8718).,Dineen TA, Chen K, Cheng AC, Derakhchan K, Epstein O, Esmay J, Hickman D, Kreiman CE, Marx IE, Wahl RC, Wen PH, Weiss MM, Whittington DA, Wood S, Fremeau RT Jr, White RD, Patel VF J Med Chem. 2014 Dec 11;57(23):9811-31. doi: 10.1021/jm5012676. Epub 2014 Nov 14. PMID:25363711<ref>PMID:25363711</ref>
-Authors: Whittington, D.A., Long, A.M.
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
-Description: Crystal structure of BACE1 in complex with a 2-aminooxazoline 4-azaxanthene inhibitor
+== References ==
-[[Category: Unreleased Structures]]
+<references/>
-[[Category: Long, A.M]]
+__TOC__
-[[Category: Whittington, D.A]]
+</StructureSection>
+[[Category: Memapsin 2]]
+[[Category: Long, A M]]
+[[Category: Whittington, D A]]
+[[Category: Alzheimer's disease]]
+[[Category: Amyloid precursor protein]]
+[[Category: App]]
+[[Category: Aspartyl protease]]
+[[Category: Brain]]
+[[Category: Hydrolase-hydrolase inhibitor complex]]

4rcd

From Proteopedia

Revision as of 16:52, 21 January 2015

Crystal structure of BACE1 in complex with a 2-aminooxazoline 4-azaxanthene inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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