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PDE4 inhibitors have been in development as a novel anti‐inflammatory therapy since the 1980s with asthma and chronic obstructive pulmonary disease (COPD) being primary indications. Despite initial optimism, none have yet reached the market. In most cases, the development of PDE4 inhibitors of various structural classes, including cilomilast, filaminast, lirimilast, piclamilast, tofimilast, AWD‐12‐281 (aka GSK 842470), CDP840, CI‐1018, D‐4418, IC485, L‐826,141, SCH 351391 and V11294A has been discontinued due to lack of efficacy. A primary problem is the low therapeutic ratio of these compounds, which severely limits the dose that can be given. Indeed, for many of these compounds it is likely that the maximum tolerated dose is either sub‐therapeutic or at the very bottom of the efficacy dose‐response curve. Therefore, the challenge is to overcome this limitation. It is, therefore, encouraging that many ‘new(er)’ PDE4 inhibitors in development are reported to have an improved therapeutic window including tetomilast, oglemilast, apremilast, ONO 6126, IPL‐512602 and IPL‐455903 (aka HT‐0712), although the basis for their superior tolerability has not been disclosed. In addition, other approaches are possible that may allow the anti‐inflammatory activity of PDE inhibitors to be realized. Accordingly, this Commentary endorses the view of Spina (2008), published in the current issue of the British Journal of Pharmacology, that the therapeutic utility of PDE4 inhibitors to suppress inflammation still remains a viable concept. British Journal of Pharmacology (2008) 155, 288–290; doi:fn1; published online 28 July 2008

Glucocorticoids are commonly prescribed to treat inflammation of the respiratory system; however, they are mostly ineffective for controlling chronic obstructive pulmonary disease (COPD)-associated inflammation. This study aimed to elucidate the molecular mechanisms responsible for such glucocorticoid inefficacy in COPD, which may be instrumental to providing better patient outcomes. Roflumilast is a selective phosphodiesterase-4 (PDE4) inhibitor with anti-inflammatory properties in severe COPD patients who have a history of exacerbations. Roflumilast has a suggested ability to mitigate glucocorticoid resistance, but the mechanism is unknown. To understand the mechanism that mediates roflumilast-induced restoration of glucocorticoid sensitivity in COPD, we tested the role of glucocorticoid receptor α (GRα). Roflumilast's effects on GRα expression and transcriptional activity were assessed in bronchial epithelial cells from COPD patients. We found that both GRα expression and activity are downregulated in bronchial epithelial cells from COPD patients and that roflumilast stimulates both GRα mRNA synthesis and GRα's transcriptional activity in COPD bronchial epithelial cells. We also demonstrate that roflumilast enhances dexamethasone's ability to suppress pro-inflammatory mediator production, in a GRα-dependent manner. Our findings highlight the significance of roflumilast-induced GRα upregulation for COPD therapeutic strategies by revealing that roflumilast restores glucocorticoid sensitivity by sustaining GRα expression.

Phosphodiesterase-4 (PDE4) inhibitors have broad anti-inflammatory activity, inhibiting the airway inflammation associated with chronic obstructive pulmonary disease (COPD), especially by reducing airway neutrophils that are key cells in COPD. A careful evaluation of the results of several meta-analyses allows us to consider the use of PDE4 inhibitors as very important in those patients with COPD who are particularly susceptible to exacerbations, the so-called ‘frequent exacerbators’. Consequently, PDE4 inhibitors should be used earlier and more frequently than is the case today, but they are prescribed sporadically because of side effects. Several strategies are conceivable to avoid side effects, but, unfortunately, many of these approaches are yet to be successfully translated into clinical effectiveness after several decades of research. A novel alternative approach is to administer multiple drugs simultaneously or drugs capable of two distinct primary pharmacological actions based on distinct pharmacophores (bifunctional drugs) in order to produce additive or synergistic effects and, consequently, to dispense these drugs at lower doses, inducing fewer side effects. The fact that we have realized that there is a need to target simultaneously more PDEs unquestionably represents an advance in the possible use of PDE inhibitors. Actually, the possibility that multivalent (multifunctional) ligands, which feature two or more pharmacophores, may deliver superior efficacy is an approach that is being explored. Recognizing the role of specific targeted therapy aimed at subcellular domains has changed our understanding of the use of PDE inhibitors, and offers an opportunity to improve both the therapeutic tolerability and efficacy of these drugs.

Pathogenic studies have revealed that phosphodiesterase 4 (PDE4) plays a key role in psoriasis inflammation. This narrative review evaluates roflumilast, a potent PDE4 inhibitor available in oral and topical formulations, as a repurposed therapeutic for plaque psoriasis. To synthesize the mechanism of action, efficacy, safety, and clinical application of roflumilast, highlighting recent evidence and its position relative to existing therapies. We systematically searched PubMed, Scopus, Web of Science, and Cochrane Library from inception to early 2026 using keywords including \"roflumilast\", \"PDE4 inhibitor\", and \"plaque psoriasis\". Both oral and topical formulations achieve clinically meaningful improvements in PASI and IGA scores with favorable tolerability. Roflumilast represents a convenient, cost-effective, and practical option, especially for sensitive sites and comorbid patients, although larger head-to-head trials against biologics are still needed.

Since the early 1980s, phosphodiesterase 4 (PDE4) has been an attractive target for the treatment of inflammation-based diseases. Several scientific advancements, by both academia and pharmaceutical companies, have enabled the identification of many synthetic ligands for this target, along with the acquisition of precise information on biological requirements and linked therapeutic opportunities. The transition from pre-clinical to clinical phase was not easy for the majority of these compounds, mainly due to their significant side effects, and it took almost thirty years for a PDE4 inhibitor to become a drug i.e., Roflumilast, used in the clinics for the treatment of chronic obstructive pulmonary disease. Since then, three additional compounds have reached the market a few years later: Crisaborole for atopic dermatitis, Apremilast for psoriatic arthritis and Ibudilast for Krabbe disease. The aim of this review is to provide an overview of the compounds that have reached clinical trials in the last ten years, with a focus on those most recently developed for respiratory, skin and neurological disorders.

Cyclic nucleotide phosphodiesterases 4 (PDE4) are a family of enzymes which specifically promote the hydrolysis and degradation of cAMP. The inhibition of PDE4 enzymes has been widely investigated as a possible alternative strategy for the treatment of a variety of respiratory diseases, including chronic obstructive pulmonary disease and asthma, as well as psoriasis and other autoimmune disorders. In this context, the identification of new molecules as PDE4 inhibitors continues to be an active field of investigation within drug discovery. This review summarizes the medicinal chemistry journey in the design and development of effective PDE4 inhibitors, analyzed through chemical classes and taking into consideration structural aspects and binding properties, as well as inhibitory efficacy, PDE4 selectivity and the potential as therapeutic agents.

ObjectiveWe investigated whether the normal human spinal enthesis contained resident myeloid cell populations, capable of producing pivotal proinflammatory cytokines including tumour necrosis factor (TNF) and interleukin (IL)-23 and determined whether these could be modified by PDE4 inhibition.MethodsNormal human enthesis soft tissue (ST) and adjacent perientheseal bone (PEB) (n=15) were evaluated using immunohistochemistry (IHC), digested for myeloid cell phenotyping, sorted and stimulated with different adjuvants (lipopolysaccharide and mannan). Stimulated enthesis fractions were analysed for inducible production of spondyloarthropathy disease-relevant mediators (IL-23 full protein, TNF, IL-1β and CCL20). Myeloid populations were also compared with matched blood populations for further mRNA analysis and the effect of PDE4 inhibition was assessed.ResultsA myeloid cell population (CD45+ HLADR+ CD14+ CD11c+) phenotype was isolated from both the ST and adjacent PEB and termed ‘CD14+ myeloid cells’ with tissue localisation confirmed by CD14+ IHC. The CD14− fraction contained a CD123+ HLADR+ CD11c− cell population (plasmacytoid dendritic cells). The CD14+ population was the dominant entheseal producer of IL-23, IL-1β, TNF and CCL20. IL-23 and TNF from the CD14+ population could be downregulated by a PDE4I and other agents (histamine and 8-Bromo-cAMP) which elevate cAMP. Entheseal CD14+ cells had a broadly similar gene expression profile to the corresponding CD14+ population from matched blood but showed significantly lower CCR2 gene expression.ConclusionsThe human enthesis contains a CD14+ myeloid population that produces most of the inducible IL-23, IL-1β, TNF and CCL20. This population has similar gene expression profile to the matched blood CD14+ population.

Clinicians and researchers are exploring safer and novel treatment strategies for treating the ever-prevalent Parkinson’s disease (PD) across the globe. Several therapeutic strategies are used clinically for PD, including dopamine replacement therapy, DA agonists, MAO-B blockers, COMT blockers, and anticholinergics. Surgical interventions such as pallidotomy, particularly deep brain stimulation (DBS), are also employed. However, they only provide temporal and symptomatic relief. Cyclic adenosine monophosphate (cAMP) is one of the secondary messengers involved in dopaminergic neurotransmission. Phosphodiesterase (PDE) regulates cAMP and cGMP intracellular levels. PDE enzymes are subdivided into families and subtypes which are expressed throughout the human body. PDE4 isoenzyme- PDE4B subtype is overexpressed in the  substantia nigra  of the brain. Various studies have implicated multiple cAMP-mediated signaling cascades in PD, and PDE4 is a common link that can emerge as a neuroprotective and/or disease-modifying target. Furthermore, a mechanistic understanding of the PDE4 subtypes has provided perceptivity into the molecular mechanisms underlying the adverse effects of phosphodiesterase-4 inhibitors (PDE4Is). The repositioning and development of efficacious PDE4Is for PD have gained much attention. This review critically assesses the existing literature on PDE4 and its expression. Specifically, this review provides insights into the interrelated neurological cAMP-mediated signaling cascades involving PDE4s and the potential role of PDE4Is in PD. In addition, we discuss existing challenges and possible strategies for overcoming them. Graphical Abstract

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on the development of oral therapies with improved efficacy and safety compared with available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate to severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways such as AhR, PDE-4, and Jak-STAT. Tapinarof (an AhR modulator) and roflumilast (a PDE-4 inhibitor) have exhibited favorable efficacy and safety outcomes and have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis, especially those that are currently under evaluation and development for the treatment of psoriasis.

Phosphodiesterase 4 (PDE4) is an enzyme that specifically hydrolyzes the second messenger cAMP and has a critical role in the regulation of a variety of cellular functions. In recent years, PDE4 has attracted great interest in cancer research, and its role in tumorigenesis and development has been gradually elucidated. Research indicates that abnormal expression or heightened activity of PDE4 is associated with the initiation and progression of multiple cancers, including lung, colorectal, and hematological cancers, by facilitating cell proliferation, migration, invasion, and anti-apoptosis. Moreover, PDE4 also influences the tumor immune microenvironment, significantly immune evasion by suppressing anti-tumor immune responses, reducing T-cell activation, and promoting the polarization of tumor-associated macrophages toward a pro-tumorigenic phenotype. However, the PDE4 family may have both oncogenic and tumor-suppressive effects, which could depend on the specific type and grade of the tumor. PDE4 inhibitors have garnered substantial interest as potential anti-cancer therapeutics, directly inhibiting tumor cell growth and restoring immune surveillance capabilities to enhance the clearance of tumor cells. Several PDE4 inhibitors are currently under investigation with the aim of exploring their potential in cancer therapy, particularly in combination strategies with immune checkpoint inhibitors, to improve therapeutic efficacy and mitigate the side effects of conventional chemotherapy. This review provides an overview of PDE4 in tumorigenesis, drug resistance, immunotherapy, and the anti-tumor actions of its inhibitors, intending to guide the exploration of PDE4 as a new target in tumor therapy.