Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket
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 <b>Z94555858</b>. By targeting the metal pocket of PDE1, a lead compound <b>3f</b> was obtained, exhibiting an IC<sub>50</sub> 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.
Authors
- Yiyi Yang (ORCID: https://orcid.org/0000-0002-1834-726X)
- Yinuo Wu (ORCID: https://orcid.org/0000-0003-3071-5333)
- Hai‐Bin Luo (ORCID: https://orcid.org/0000-0002-2163-0509)
- Qian Zhou (ORCID: https://orcid.org/0000-0002-6384-6535)
- Lingling Feng
- Qinghua Huang (ORCID: https://orcid.org/0000-0003-1080-6940)
- Chen Zhang (ORCID: https://orcid.org/0000-0002-0447-0961)
- Mei-Yan Jiang (ORCID: https://orcid.org/0000-0003-3782-5295)
Institutions
- Sun Yat-sen University (CN)
- Guangdong Pharmaceutical University (CN)
- Hainan University (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01533
- Citations
- 5
- Primary Topic
- Phosphodiesterase function and regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Hainan Province
- Hainan University