Structure-Based Optimization of Imidazopyridine Derivatives as Selective and Orally Bioavailable Phosphodiesterase 10A Inhibitors with Reduced Blood–Brain Barrier Penetration for the Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (PF) is a debilitating,
progressive,
and severe interstitial lung disease that lacks an effective treatment.
The overexpression of phosphodiesterase 10A (PDE10A) is closely associated
with the development of PF. However, few selective PDE10A inhibitors
with favorable drug-like properties are orally available for the treatment
of PF. Structure-based optimization of compound A30 has
led to the development of compound QC-3, which exhibits
an IC50 of 6.2 nM against PDE10A, excellent selectivity
among PDEs, favorable drug-like properties, and reduced blood–brain
barrier penetration. In a bleomycin-induced murine model of PF, oral
administration of QC-3 (10 mg/kg, once daily) demonstrated
superior antifibrotic efficacy compared to pirfenidone (300 mg/kg,
once daily), while exhibiting minimal cerebral residue, thereby reducing
its potential risk of central nervous system suppression. Moreover, QC-3 attenuates PF by blocking myofibroblast differentiation
through the cAMP/PKA/CREB signaling pathway, highlighting that inhibition
of PDE10A provides a novel and promising therapeutic strategy for
PF.