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

spinqualitylabelsall models 9vq3, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9vq3 is a 2 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 2.4Å Ligands: A1ETB, MG, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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