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 <b>A30</b> has led to the development of compound <b>QC-3</b>, 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 <b>QC-3</b> (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, <b>QC-3</b> 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.