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

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.