2. Academic Validation
  3. Discovery of novel azetidine-based imidazopyridines as selective and orally bioavailable inhibitors of phosphodiesterase 10A for the treatment of pulmonary arterial hypertension

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. 2025 Jun 5:290:117537. doi: 10.1016/j.ejmech.2025.117537.
Hongzhe Huang 1,  Huanxin Xue 1,  Anqi Cai 2,  Han Yuan 1,  Yufen Yao 1,  Runduo Liu 1,  Yi Yang 1,  Quan Wang 1,  Zhe Li 1,  Ting Liu 2,  Yi-You Huang 3,  Wei Dai 4,  Hai-Bin Luo 3,  Xiaozhou Zou 5,  Xiaoying Wang 6,  Lei Guo 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
  • 2 Center for Clinical Pharmacy, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China.
  • 3 Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou, 570228, China.
  • 4 Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China.
  • 5 Center for Clinical Pharmacy, Department of Pharmacy, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou, 310014, China. Electronic address: zxzlovesci@163.com.
  • 6 Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China; Guangdong Key Laboratory of Blockchain Security, Guangzhou University, Guangzhou, 510006, China. Electronic address: wxying@mail.sysu.edu.cn.
  • 7 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China. Electronic address: guolei7@mail.sysu.edu.cn.
PMID: 40138991 DOI: 10.1016/j.ejmech.2025.117537
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 IC50 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.

Keywords

Drug design; Imidazopyridine; Phosphodiesterase 10A; Pulmonary arterial hypertension; Sugen/hypoxia.

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