4pzx

From Proteopedia

(Difference between revisions)

Current revision

Synthesis, Characterization and PK/PD Studies of a Series of Spirocyclic Pyranochromene BACE1 Inhibitors

Structural highlights

4pzx is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.8Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

The development of 1,3,4,4a,5,10a-hexahydropyrano[3,4-b]chromene analogs as BACE1 inhibitors is described. Introduction of the spirocyclic pyranochromene scaffold yielded several advantages over previous generation cores, including increased potency, reduced efflux, and reduced CYP2D6 inhibition. Compound 13 (BACE1 IC50=110nM) demonstrated a reduction in CSF Abeta in wild type rats after a single dose.

Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors.,Volgraf M, Chan L, Huestis MP, Purkey HE, Burkard M, Geck Do M, Harris J, Hunt KW, Liu X, Lyssikatos JP, Rana S, Thomas AA, Vigers GP, Siu M Bioorg Med Chem Lett. 2014 Jun 1;24(11):2477-80. doi: 10.1016/j.bmcl.2014.04.012., Epub 2014 Apr 13. PMID:24780121^[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
↑ Volgraf M, Chan L, Huestis MP, Purkey HE, Burkard M, Geck Do M, Harris J, Hunt KW, Liu X, Lyssikatos JP, Rana S, Thomas AA, Vigers GP, Siu M. Synthesis, characterization, and PK/PD studies of a series of spirocyclic pyranochromene BACE1 inhibitors. Bioorg Med Chem Lett. 2014 Jun 1;24(11):2477-80. doi: 10.1016/j.bmcl.2014.04.012., Epub 2014 Apr 13. PMID:24780121 doi:http://dx.doi.org/10.1016/j.bmcl.2014.04.012

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

Categories: Homo sapiens | Large Structures | Vigers GPA

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[4pzx]] 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=4PZX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PZX FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2X5:(4R,4AR,10AR)-7-(5-CHLOROPYRIDIN-3-YL)-3,4,4A,10A-TETRAHYDRO-1H-SPIRO[1,3-OXAZOLE-4,5-PYRANO[3,4-B]CHROMEN]-2-AMINE'>2X5</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2X5:(4R,4AR,10AR)-7-(5-CHLOROPYRIDIN-3-YL)-3,4,4A,10A-TETRAHYDRO-1H-SPIRO[1,3-OXAZOLE-4,5-PYRANO[3,4-B]CHROMEN]-2-AMINE'>2X5</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</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=4pzx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4pzx OCA], [https://pdbe.org/4pzx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4pzx RCSB], [https://www.ebi.ac.uk/pdbsum/4pzx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4pzx ProSAT]</span></td></tr>
 </table>

4pzx

From Proteopedia

Current revision

Synthesis, Characterization and PK/PD Studies of a Series of Spirocyclic Pyranochromene BACE1 Inhibitors

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox