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

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

Cyclic Nucleotide Phosphodiesterases, Type 1*/antagonists & inhibitors ; Cyclic Nucleotide Phosphodiesterases, Type 1*/metabolism ; Drug Design* ; Liver Cirrhosis*/drug therapy ; Liver Cirrhosis*/pathology ; Pyrimidines*/chemical synthesis ; Pyrimidines*/pharmacology ; Pyrimidines*/chemistry ; Pyrimidines*/therapeutic use ; Phosphodiesterase Inhibitors*/pharmacology ; Phosphodiesterase Inhibitors*/chemical synthesis ; Phosphodiesterase Inhibitors*/therapeutic use ; Phosphodiesterase Inhibitors*/chemistry; Animals ; Humans ; Rats ; Male ; Structure-Activity Relationship ; Rats, Sprague-Dawley ; Molecular Docking Simulation ; Molecular Structure

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 IC 50 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.

EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 1)
0 (Pyrimidines)
0 (Phosphodiesterase Inhibitors)

Date Created: 20240426 Date Completed: 20240523 Latest Revision: 20240523

20240523

10.1021/acs.jmedchem.4c00461

38669059