View source for 9vq3


==Crystal structure of human phosphodiesterase 10A in complex with (6-fluoro-2-(1-(4-methylquinazolin-2-yl)azetidin-3-yl)imidazo[1,2-a]pyridin-3-yl)(4,7-diazaspiro[2.5]octan-7-yl)methanone==
<StructureSection load='9vq3' size='340' side='right'caption='[[9vq3]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9vq3]] 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=9VQ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9VQ3 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]] 2.4&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1ETB:4,7-diazaspiro[2.5]octan-7-yl-[6-fluoranyl-2-[1-(4-methylquinazolin-2-yl)azetidin-3-yl]imidazo[1,2-a]pyridin-3-yl]methanone'>A1ETB</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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=9vq3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9vq3 OCA], [https://pdbe.org/9vq3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9vq3 RCSB], [https://www.ebi.ac.uk/pdbsum/9vq3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9vq3 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Idiopathic pulmonary fibrosis (PF) is a debilitating, progressive, and severe interstitial lung disease that lacks an effective treatment. The overexpression of phosphodiesterase 10A (PDE10A) is closely associated with the development of PF. However, few selective PDE10A inhibitors with favorable drug-like properties are orally available for the treatment of PF. Structure-based optimization of compound A30 has led to the development of compound QC-3, which exhibits an IC(50) of 6.2 nM against PDE10A, excellent selectivity among PDEs, favorable drug-like properties, and reduced blood-brain barrier penetration. In a bleomycin-induced murine model of PF, oral administration of QC-3 (10 mg/kg, once daily) demonstrated superior antifibrotic efficacy compared to pirfenidone (300 mg/kg, once daily), while exhibiting minimal cerebral residue, thereby reducing its potential risk of central nervous system suppression. Moreover, QC-3 attenuates PF by blocking myofibroblast differentiation through the cAMP/PKA/CREB signaling pathway, highlighting that inhibition of PDE10A provides a novel and promising therapeutic strategy for PF.

Structure-Based Optimization of Imidazopyridine Derivatives as Selective and Orally Bioavailable Phosphodiesterase 10A Inhibitors with Reduced Blood-Brain Barrier Penetration for the Treatment of Idiopathic Pulmonary Fibrosis.,Zhang F, Yuan H, Yao S, Yang D, Wu J, Chen J, Wang Q, Huang YY, Luo HB, Guo L J Med Chem. 2025 Dec 11;68(23):25290-25306. doi: 10.1021/acs.jmedchem.5c02293. , Epub 2025 Nov 21. PMID:41269079<ref>PMID:41269079</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9vq3" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Guo L]]
[[Category: Huang YY]]
[[Category: Luo HB]]
[[Category: Zhang FC]]