9JDU
The crystal structure of PDE10A complexed with inhibitor 2061
This is a non-PDB format compatible entry.
Summary for 9JDU
| Entry DOI | 10.2210/pdb9jdu/pdb |
| Descriptor | cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total) |
| Functional Keywords | pde10a, selective inhibitor, hydrolase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 75792.69 |
| Authors | |
| Primary citation | Huang, H.,Xue, H.,Cai, A.,Yuan, H.,Yao, Y.,Liu, R.,Yang, Y.,Wang, Q.,Li, Z.,Liu, T.,Huang, Y.Y.,Dai, W.,Luo, H.B.,Zou, X.,Wang, X.,Guo, L. Discovery of novel azetidine-based imidazopyridines as selective and orally bioavailable inhibitors of phosphodiesterase 10A for the treatment of pulmonary arterial hypertension. Eur.J.Med.Chem., 290:117537-117537, 2025 Cited by PubMed Abstract: Pulmonary arterial hypertension (PAH) is a chronic, progressive disorder of the pulmonary vasculature characterized by associated pulmonary and cardiac remodeling. Phosphodiesterase 10A (PDE10A) plays a crucial role in regulating cAMP concentration, thereby influencing pulmonary inflammation and pulmonary vascular remodeling. However, there is a lack of ideal PDE10A selective inhibitors available for PAH treatment. Herein, we employed structure-based drug design to develop a series of azetidine-based imidazopyridines, among which A30 demonstrated an IC value of 3.5 nmol/L against PDE10A with high selectivity over other PDEs, low blood-brain barrier permeability, and improved drug-like properties. Oral administration of A30 exhibited significant anti-PAH effects not only in monocrotaline-induced rats, but also in Sugen/hypoxia(Su/Hx)-induced PH mice. Our findings indicate that A30 inhibits PDE10A to suppress pulmonary vascular remodeling through the activation of cAMP-associated signaling pathways. PubMed: 40138991DOI: 10.1016/j.ejmech.2025.117537 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.3000175118 Å) |
Structure validation
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