2. Academic Validation
  3. Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket

Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket

  • J Med Chem. 2024 Nov 28;67(22):20203-20213. doi: 10.1021/acs.jmedchem.4c01533.
Mei-Yan Jiang 1,  Chen Zhang 2,  Qing-Hua Huang 1,  Ling-Ling Feng 1,  Yi-Yi Yang 3,  Qian Zhou 3,  Hai-Bin Luo 3 4,  Yinuo Wu 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China.
  • 2 School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, 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, Hainan, China.
  • 4 Song Li' Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya 572000, China.
PMID: 39546471 DOI: 10.1021/acs.jmedchem.4c01533
Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood. This study carried out a step-by-step optimization of a dihydropyrimidine hit Z94555858. By targeting the metal pocket of PDE1, a lead compound 3f was obtained, exhibiting an IC50 value of 11 nM against PDE1, moderate selectivity over Other PDEs, and significant anti-fibrotic effects in bleomycin-induced pulmonary fibrosis rats. The structure-activity relationship study aided by molecular docking revealed that forming halogen bonds with water in the metal pocket greatly enhanced the PDE1 inhibition, providing a novel strategy for further rational design of PDE1 inhibitors.

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