Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases

Abstract

Phosphodiesterase-4 (PDE4), mainly present in immune cells, epithelial cells, and brain cells, manifests as an intracellular non-receptor enzyme that modulates inflammation and epithelial integrity. Inhibition of PDE4 is predicted to have diverse effects via the elevation of the level of cyclic adenosine monophosphate (cAMP) and the subsequent regulation of a wide array of genes and proteins. It has been identified that PDE4 is a promising therapeutic target for the treatment of diverse pulmonary, dermatological, and severe neurological diseases. Over the past decades, numerous PDE4 inhibitors have been designed and synthesized, among which roflumilast, apremilast, and crisaborole were approved for the treatment of inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively. It is regrettable that the dramatic efficacies of a drug are often accompanied by adverse effects, such as nausea, emesis, and gastrointestinal reactions. However, substantial advances have been made to mitigate the adverse effects and obtain better benefit-to-risk ratio. This review highlights the dialectical role of PDE4 in drug discovery and the disquisitive details of certain PDE4 inhibitors to provide an overview of the topics that still need to be addressed in the future.

Keywords: apremilast; atopic dermatitis; crisaborole; inflammatory airway diseases; inflammatory bowel disease; phosphodiesterase-4; psoriasis; roflumilast.

Figure 1

Pathological manifestations and PDE4 inhibitors in inflammatory diseases.

Figure 2

Mode of PDE4 inhibition in the regulation of inflammatory responses. (A) PDE4 regulates the production of pro-inflammatory and anti-inflammatory cytokines and cell proliferation via the degradation of cAMP. PDE4 inhibition leads to the accumulation of intracellular cAMP, which can activate protein kinase A (PKA) and the exchange protein 1/2 activated by cAMP (Epac1/2). PKA activation results in the phosphorylation of cAMP-responsive element binding protein (CREB) and activating transcription factor 1 (ATF-1), leading to the increase in anti-inflammatory cytokines. The transcriptional activity of NF-κB can be regulated by PKA activation through the modulation of its interaction with CREB binding protein (CBP) or p300; meanwhile, PKA activation can interfere with the synthesis of B-cell lymphoma 6 protein (Bcl-6)-mediated pro-inflammatory cytokines and the proliferation of immune cells. Compartmentalization of intracellular cAMP contributes to the Epac signalosome of transcription factors, small GTPases (Rap1), which serves as a promising alternative mechanism to target inflammation and proliferation. (B) PDE4 inhibition has a broad spectrum of anti-inflammatory effects. Owing to the distribution of PDE4 in the human body, PDE4 inhibition can inhibit inflammatory responses from macrophages, DCs, Th1, Th2, and Th17 cells, increase the production of anti-inflammatory cytokines from macrophages, and interfere with the phenotype and function of B cells as well. Moreover, PDE4 inhibition can also promote the barrier function of keratinocytes and epithelial cells via suppression of the inflammatory mediator production.

Figure 3

Approved PDE4 inhibitors for the treatment of inflammatory diseases. (A) Roflumilast was approved in the EU (2010) and USA (2011) for the treatment to reduce the risk of COPD exacerbations in patients with severe COPD associated with chronic bronchitis and a history of exacerbations. (B) Apremilast was approved in USA (2014) for adult patients with active psoriatic arthritis and patients with moderate-to-severe plaque psoriasis who were candidates for phototherapy or systemic therapy. (C) Crisaborole was approved in USA (2016) for topical treatment of mild-to-moderate atopic dermatitis in patients aged 2 years and older.