Structural Modifications of Nimodipine Lead to Novel PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects

  • J Med Chem. 2022 Jun 23;65(12):8444-8455. doi: 10.1021/acs.jmedchem.2c00458.
Meng-Xing Huang  1 ,  Yi-Jing Tian  1 ,  Chuan Han  1 ,  Run-Duo Liu  1 ,  Xi Xie  2 ,  Yijun Yuan  2 ,  Yi-Yi Yang  1 ,  Zhe Li  1 ,  Jianwen Chen  1 ,  Hai-Bin Luo  1  2  3 ,  Yinuo Wu  1
Affiliations
  • 1. School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
  • 2. Key Laboratory of Tropical Biological Resources of Ministry of Education and One Health Institute, School of Life and Pharmaceutical Sciences, Hainan University, Haikou, Hainan 570228, China.
  • 3. Song Li' Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya 572000, China.
PMID: 35666471 DOI: 10.1021/acs.jmedchem.2c00458
Abstract

Our previous research demonstrated that phosphodiesterase-1 (PDE1) could work as a potential target against idiopathic pulmonary fibrosis. Nimodipine, a calcium antagonist commonly used to improve hypertension, was reported to have inhibition against PDE1. Herein, a series of nimodipine analogues were discovered as novel selective and potent PDE1 inhibitors after structural modifications. Compound 2g exhibited excellent inhibitory activity against PDE1C (IC50 = 10 nM), high selectivity over Other PDEs except for PDE4, and weak Calcium Channel antagonistic activity. Administration of compound 2g exhibited remarkable therapeutic effects in a rat model of pulmonary fibrosis induced by bleomycin and prevented myofibroblast differentiation induced by TGF-β1. The expressions of PDE1B and PDE1C were found to be increased and concentrated in the focus of fibrosis. Compound 2g increased the levels of 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) in the lungs of rats with pulmonary fibrosis, supporting the fact that the anti-fibrosis effects of 2g were through the regulation of cAMP and cGMP.

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