View source for 8bpy


==X-RAY STRUCTURE OF PDE9A IN COMPLEX WITH Inhibitor 13A==
<StructureSection load='8bpy' size='340' side='right'caption='[[8bpy]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8bpy]] is a 2 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=8BPY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8BPY 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]] 3.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=R4I:(8~{S})-6-[2-(2,3-dihydroindol-1-yl)-2-oxidanylidene-ethyl]-4-(4-methylphenyl)-2-oxidanylidene-8-propyl-1,5,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile'>R4I</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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=8bpy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8bpy OCA], [https://pdbe.org/8bpy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8bpy RCSB], [https://www.ebi.ac.uk/pdbsum/8bpy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8bpy ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Despite advances in the treatment of heart failure in recent years, options for patients are still limited and the disease is associated with considerable morbidity and mortality. Modulating cyclic guanosine monophosphate levels within the natriuretic peptide signaling pathway by inhibiting PDE9A has been associated with beneficial effects in preclinical heart failure models. We herein report the identification of BAY-7081, a potent, selective, and orally bioavailable PDE9A inhibitor with very good aqueous solubility starting from a high-throughput screening hit. Key aspect of the optimization was a switch in metabolism of our lead structures from glucuronidation to oxidation. The switch proved being essential for the identification of compounds with improved pharmacokinetic profiles. By studying a tool compound in a transverse aortic constriction mouse model, we were able to substantiate the relevance of PDE9A inhibition in heart diseases.

BAY-7081: A Potent, Selective, and Orally Bioavailable Cyanopyridone-Based PDE9A Inhibitor.,Meibom D, Micus S, Andreevski AL, Anlauf S, Bogner P, von Buehler CJ, Dieskau AP, Dreher J, Eitner F, Fliegner D, Follmann M, Gericke KM, Maassen S, Meyer J, Schlemmer KH, Steuber H, Tersteegen A, Wunder F J Med Chem. 2022 Dec 22;65(24):16420-16431. doi: 10.1021/acs.jmedchem.2c01267. , Epub 2022 Dec 7. PMID:36475653<ref>PMID:36475653</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8bpy" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Steuber H]]