| Autor: |
Jiang MY; State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China., Zhang C; School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China., Huang QH; State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China., Feng LL; State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China., Yang YY; 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., Zhou Q; 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., Luo HB; 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.; Song Li' Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya 572000, China., Wu Y; State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China. |
| Abstrakt: |
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 IC 50 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. |
