Discovery of Novel Selective and Orally Bioavailable Phosphodiesterase-1 Inhibitors for the Efficient Treatment of Idiopathic Pulmonary Fibrosis.
J Med Chem
; 63(14): 7867-7879, 2020 07 23.
Article
in En
| MEDLINE
| ID: mdl-32603117
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease lacking effective therapy. To identify whether phosphodiesterase-1 (PDE1) inhibition could act as a novel target for the treatment of IPF, hit-to-lead structural optimizations were performed on the PDE9/PDE1 dual inhibitor (R)-C33, leading to compound 3m with an IC50 of 2.9 nM against PDE1C, excellent selectivity across PDE subfamilies, reasonable drug-like properties, and remarkable pharmacodynamic effects as an anti-IPF agent. Oral administration of compound 3m (10 mg/kg) exerted more significant anti-pulmonary fibrosis effects than pirfenidone (150 mg/kg) in a bleomycin-induced IPF rat model and prevented transforming growth factor-ß-induced fibroblast-to-myofibroblast conversion in vitro, indicating that PDE1 inhibition could serve as a novel target for the efficient treatment of IPF.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phosphodiesterase Inhibitors
/
Pyrazoles
/
Pyrimidinones
/
Cyclic Nucleotide Phosphodiesterases, Type 1
/
Idiopathic Pulmonary Fibrosis
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2020
Document type:
Article