Design, Synthesis, and Evaluation of Dihydropyrimidine Derivatives as Selective PDE1 Inhibitors for the Treatment of Liver Fibrosis

Liver fibrosis is a common pathological feature of most
chronic
liver diseases with no effective drugs available. Phosphodiesterase
1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent
target for liver fibrosis by regulating the concentration of cAMP
and cGMP. However, there are few PDE1 selective inhibitors, and none
has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected
as the hit by virtual screening. A hit-to-lead structural modification
led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity
over other PDEs, as well as good safety properties. Administration
of 13h exerted significant anti-liver fibrotic effects
in bile duct ligation-induced fibrosis rats, which also prevented
TGF-β-induced myofibroblast differentiation in vitro, confirming
that PDE1 could work as a potential target for liver fibrosis.