9JDU

The crystal structure of PDE10A complexed with inhibitor 2061

これはPDB形式変換不可エントリーです。

9JDU の概要

• エントリーDOI: 10.2210/pdb9jdu/pdb
• 分子名称: cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• 機能のキーワード: pde10a, selective inhibitor, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75792.69

構造登録者

Huang, Y.-Y.,Guo, L.,Luo, H.-B. (登録日: 2024-09-01, 公開日: 2025-06-25)

主引用文献

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

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: 40138991
DOI: 10.1016/j.ejmech.2025.117537

実験手法

X-RAY DIFFRACTION (2.3000175118 Å)