Phosphodiesterase-4 Inhibitors in COPD Therapy: A Review of Mechanisms, Limitations, and Emerging Opportunities
DOI:
https://doi.org/10.71193/jmct.20250009Keywords:
COPD, phosphodiesterase-4 inhibitors, inflammation, roflumilast, drug developmentAbstract
Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory disease with a high global morbidity rate and irreversible airflow limitation. Without addressing the underlying inflammation, current therapies mainly reduce symptoms. By examining the development, mechanisms, and therapeutic potential of phosphodiesterase-4 (PDE4) inhibitors in COPD, this review highlights developments, obstacles, and new approaches to clinical translation. PDE4 inhibitors suppress the release of inflammatory mediators and promote bronchodilation by increasing intracellular cyclic adenosine monophosphate (cAMP) levels. However, the extensive distribution of PDE4 in non-pulmonary tissues limits the use of treatment by causing gastrointestinal and neuropsychiatric side effects. The literature from 1977 to 2025 shows that while second-generation agents like roflumilast and cilomilast showed improved selectivity but only slight benefits, early compounds like rolipram showed efficacy but poor tolerability. Isoform-selective PDE4B targeting, inhaled delivery methods, and dual PDE3/4 inhibition are recent developments that present encouraging avenues for improving safety and efficacy. PDE4 inhibitors offer important mechanistic insight into COPD inflammation, despite the fact that clinical progress is still limited. Future developments will rely on better isoform specificity, optimized pulmonary formulations, and biomarker-guided patient selection. PDE4 inhibitors may progress from experimental anti-inflammatory drugs to precision treatments that can alter the course of COPD with these improvements.
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