Next Generation PDE4 Inhibitors that Selectively Target PDE4B/D Subtypes: A Narrative Review

Abstract

For decades, topical corticosteroids have been the mainstay of treatment for mild-to-moderate inflammatory skin diseases, even though only short-term use is approved for these agents and systemic inflammation is not addressed. Increased understanding of the immunopathogenesis of these conditions, especially for psoriasis and atopic dermatitis, has facilitated the development of antibody-based drugs that neutralize single key cytokines or their associated receptors, such as interleukin (IL)-17A/F, IL-23, and IL-17RA in psoriasis and IL-13 and IL-4Rα in atopic dermatitis. However, oral therapy is still preferred by many patients owing to the ease of use and needle-free administration. Phosphodiesterase 4 (PDE4) inhibitors have been approved for both oral and topical use for inflammatory skin diseases. In this review, we present a summary of an emerging class of selective PDE4B/D inhibitors under clinical development and compare the differences in selectivity of this new generation of PDE4 inhibitors with the less selective currently approved PDE4 inhibitors.

Keywords: Nerandomilast; Orismilast; PDE4 inhibitors; PDE4B; PDE4D; PF-07038124; Zatolmilast.

Fig. 1

Schematic illustration of how PDE4 inhibitors and cAMP are involved in resolving inflammation. Increased level of cAMP inhibits the production of pro-inflammatory cytokines through simultaneous inhibition of PKA-NFkB and Epac1/2-NFkB pathways; and promotes the production of anti-inflammatory mediators by activation of the PKA-CREB pathway. The intracellular level of cAMP is mainly controlled by the activity of adenylyl cyclase (AC) and phosphodiesterase 4 (PDE4). Upon stimulation, AC increases cAMP levels by converting ATP to cAMP. PDE4 controls the amplitude and duration of the cAMP signal by catalyzing the degradation of cAMP to AMP. Inhibition of PDE4 increases the intracellular levels of cAMP. Adenylyl cyclase (AC), phosphodiesterase 4 (PDE4), protein kinase A (PKA), exchange protein 1/2 activated by cAMP (Epac1/2), phosphorylated cAMP-responsive element binding protein (pCREB), nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), inhibitor of PDE4 (PDE4i) The figure was created with assistance from Erik Nylund, VisualizeThat AB

Fig. 2

Schematic illustration of the regulation of PDE4 isoforms in stimulated T cells and the importance of inhibiting short isoforms to prevent production of inflammatory cytokines in skin. The figure is based on PDE4 isoform data obtained using anti-CD3/CD28 stimulation of CD4⁺ T cells [10]. The key findings were as follows: (i) The upregulation of short PDE4 splice variants was reported to account for the induction of PDE4 activity in stimulated CD4⁺ T cells; (ii) PDE4B2 was transiently upregulated; (iii) PDE4D1/D2 were upregulated in a time-dependent manner; (iv) PDE4B1/B3 were downregulated over time; (v) Long PDE4A/4D isoforms were unchanged; and (vi) Short isoforms of PDE4A/PDE4C and long isoforms of PDE4C were not detected. Inhibition of PDE4B2 and PDE4D1/D2 leads to increased levels of cAMP and reduced levels of disease driving cytokines in the skin The figure was created with assistance from Erik Nylund, VisualizeThat AB