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 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.