Discovery of Potent Phosphodiesterase‑9 Inhibitors for the Treatment of Hepatic Fibrosis

Hepatic fibrosis commonly exists
in chronic liver disease and would
eventually develop to cirrhosis and liver cancer with high fatality.
Phosphodiesterase-9 (PDE9) has attracted profound attention as a drug
target because of its highest binding affinity among phosphodiesterases
(PDEs) with cyclic guanosine monophosphate. However, no published
study has reported PDE9 inhibitors as potential agents against hepatic
fibrosis yet. Herein, structural modification from a starting hit LL01 led to lead 4a, which exhibited an IC50 value of 7.3 nM against PDE9, excellent selectivity against
other PDE subfamilies, and remarkable microsomal stability. The cocrystal
structure of PDE9 with 4a revealed an important residue,
Phe441, capable of improving the selectivity of PDE9 inhibitors. Administration
of 4a exerted a significant antifibrotic effect in bile
duct-ligation-induced rats with hepatic fibrosis and transforming
growth factor-β-induced fibrogenesis. This therapeutic effect
was indeed achieved by selectively inhibiting PDE9 rather than other
PDE isoforms, identifying PDE9 inhibitors as potential agents against
hepatic fibrosis.