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Inhalable Carbonyl Sulfide Donor-Hybridized Selective Phosphodiesterase 10A Inhibitor for Treating Idiopathic
Quan Wang1, Xinyue Liu1, Han Yuan1
1School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, P. R. China.
Abstract:
Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited a novel carbonyl sulfide (COS)/hydrogen sulfide (H2S)-donor hybrid PDE10A inhibitor called COS-2080 with a well-defined mechanism of H2S-releasing action. It exhibited highly potent inhibitory activity against PDE10A and excellent PDE subfamily selectivity. Moreover, COS-2080 demonstrated significant antifibrotic effects by inhibiting cell proliferation and mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation called COS-2080-DPI has been developed using the ultrasonic spray freeze drying (USFD) technique, demonstrating significant antifibrotic efficacy in mice with bleomycin-induced PF at a dosage approximately 600 times lower than pirfenidone. This remarkable antifibrotic efficacy of COS-2080 on TGF-β1-induced FMT could be primarily attributed to its inhibition of the Smad2/Smad3 phosphorylation. Moreover, COS-2080 effectively attenuated fibrosis in MRC-5 cells by activating the cAMP/protein kinase A (PKA)/CREB pathway and potentially increasing levels of p53 protein. Our findings suggest that effective inhibition of PDE10A potentially confers a protective effect on FMT in PF by impeding TGF-β signaling and activating the cAMP/PKA/CREB/p53 axis.
Insights
A novel PDE10A inhibitor, COS-2080, shows potent antifibrotic effects in pulmonary fibrosis models by targeting TGF-β signaling. This inhibitor, delivered via inhalation, offers a promising new therapeutic strategy for this incurable lung disease.
Area of Science:
- Pharmacology
- Pulmonary Medicine
- Biochemistry
Background:
- Idiopathic pulmonary fibrosis (IPF) is a severe lung disease with limited treatment options.
- Phosphodiesterase 10A (PDE10A) overexpression is implicated in pulmonary fibrosis (PF).
- The role of selective PDE10A inhibitors in the TGF-β/Smad pathway in PF is not fully understood.
Purpose of the Study:
- To investigate the antifibrotic effects of a novel PDE10A inhibitor, COS-2080.
- To elucidate the mechanism of action of COS-2080 on the TGF-β/Smad signaling pathway.
- To develop and evaluate an inhaled formulation of COS-2080 for PF treatment.
Main Methods:
- Development of a novel carbonyl sulfide (COS)/hydrogen sulfide (H2S)-donor hybrid PDE10A inhibitor (COS-2080).
- Assessment of PDE10A inhibitory activity and selectivity.
- Evaluation of antifibrotic effects in vitro (cell proliferation, fibroblast-to-myofibroblast transition) and in vivo (bleomycin-induced PF model in mice).
- Analysis of signaling pathways including TGF-β/Smad, cAMP/PKA/CREB, and p53.
Main Results:
- COS-2080 demonstrated potent and selective PDE10A inhibition.
- COS-2080 significantly inhibited cell proliferation and fibroblast-to-myofibroblast transition (FMT).
- An inhaled formulation (COS-2080-DPI) showed remarkable efficacy in a mouse model of PF, requiring a much lower dose than pirfenidone.
- Antifibrotic effects were linked to Smad2/Smad3 phosphorylation inhibition and activation of the cAMP/PKA/CREB/p53 pathway.
Conclusions:
- COS-2080 is a potent PDE10A inhibitor with significant antifibrotic properties.
- Inhibition of PDE10A by COS-2080 effectively mitigates PF by modulating TGF-β signaling and activating the cAMP/PKA/CREB/p53 axis.
- COS-2080-DPI represents a promising inhaled therapeutic candidate for treating pulmonary fibrosis.
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