Structural Insights: What Makes Some PDE4 Inhibitors More Effective in Inflammatory Dermatoses

J Clin Aesthet Dermatol. 2025;18(7):18–21.

by Naiem T. Issa, MD, PhD; Jimin Wang, PhD; Ailish Hanly, MD; Minh Ho, MS; Sabine Obagi, BA; Giovanni Damiani, MD, PhD; James Q. Del Rosso, DO; Youna Kang, PharmD; and Christopher G. Bunick, MD, PhD

Dr. Issa is with Forefront Dermatology in Vienna, Virginia; the University of Miami Miller School of Medicine in Miami, Florida; the Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery in Miami, Florida; and the Department of Dermatology at George Washington University School of Medicine and Health Sciences in Washington, District of Columbia. Drs. Wang and Bunick are with the Department of Molecular Biophysics and Biochemistry at Yale University in New Haven, Connecticut. Drs. Bunick, Kang, Hanly, and Mr. Ho are with the Department of Dermatology at Yale School of Medicine in New Haven, Connecticut. Ms. Obagi is with the College of Medicine at the University of Arizona in Tucson, Arizona. Dr. Damiani is with the Department of Biomedical, Surgical, and Dental Sciences at the University of Milan in Milan, Italy; and Fondazione IRCCS CA’ Granda Ospedale Maggiore Policlinico in Milan, Italy. Dr. Del Rosso is with JDR Dermatology Research in Las Vegas, Nevada; Advanced Dermatology and Cosmetic Surgery in Maitland, Florida; and the Department of Dermatology at Touro University Nevada in Henderson, Nevada. Dr. Kang is with Yale-New Haven Hospital Pharmacy in New Haven, Connecticut. Dr. Bunick is also with the Program in Translational Biomedicine at Yale School of Medicine in New Haven, Connecticut.

FUNDING: No funding was provided for this article.

DISCLOSURES: Drs. Issa and Bunick have served as consultants for Amgen, Arcutis, and Pfizer.

Abstract: Psoriasis, seborrheic dermatitis, and atopic dermatitis are chronic inflammatory skin diseases affecting millions of people in the United States and worldwide across the human lifespan. The immune pathways underlying the pathogenesis of these dermatoses include Type I (IFN-γ, TNF-α), Type II (IL-4, IL-5, IL-13), and Type III (IL- 17A/F, IL-22, IL-23) cytokines. These cytokines function downstream of the enzyme phosphodiesterase-IV (PDE4), which makes PDE4 an upstream central regulator of inflammatory dermatoses. PDE4, therefore, is a key drug target for alleviating inflammatory skin diseases. In this brief review, we discuss and simplify into clinically relevant terminology the molecular findings of a 2024 study by Wang et al, which analyzed the structural properties of dermatologic PDE4 inhibitors and thereby provided molecular rationale as to why roflumilast has the greatest potency and is highly efficacious across multiple inflammatory dermatoses. Keywords: Psoriasis, seborrheic dermatitis, atopic dermatitis, roflumilast, apremilast, crisaborole, cAMP

Introduction

Psoriasis, seborrheic dermatitis, and atopic dermatitis are chronic inflammatory skin diseases affecting millions of people in the United States and worldwide across the human lifespan. The immune pathways underlying the pathogenesis of these dermatoses include Type I (interferon [IFN]-γ, tumor necrosis factor [TNF]-α), Type II (interleukin [IL]-4, IL-5, IL-13), and Type III (IL-17A/F, IL-22, IL-23) cytokines.^1,2 These cytokines function downstream of the enzyme phosphodiesterase-IV (PDE4), which makes PDE4 an upstream central regulator of inflammatory dermatoses.^3,4 PDE4, therefore, is a key drug target for alleviating inflammatory skin diseases.

In this brief review, we discuss and simplify into clinically relevant terminology the molecular findings of a study by Wang et al⁵ published in the Journal of Investigative Dermatology (JID), which analyzed the structural properties of dermatologic PDE4 inhibitors and thereby provided molecular rationale as to why roflumilast has the greatest potency among PDE4 inhibitors and is highly efficacious across multiple inflammatory dermatoses.

Understanding PDE4 Inhibitors

PDE4 is functionally upstream of cytokine production in immune and non-immune cells. PDE4 inhibitors are small molecule drugs designed to bind into a specific active site on the PDE4 enzyme, preventing PDE4 from hydrolyzing (i.e., breaking down) cyclic adenosine monophosphate (cAMP) into AMP.⁶ Low cAMP triggers a pro-inflammatory cytokine cascade driving inflammatory dermatoses like psoriasis, seborrheic dermatitis, and atopic dermatitis. cAMP modulates secondary processes that result in diminished inflammation. The goal of inhibiting PDE4 is to boost cAMP concentrations, which promote an anti-inflammatory effect by suppressing transcription of pro-inflammatory cytokines. The JID study compared the binding characteristics of three United States Food and Drug Administration (FDA) approved dermatologic PDE4 inhibitors: apremilast, crisaborole, and roflumilast.

Key Structural Findings

The study⁵ focused on several structural properties of PDE4 inhibitors, including:

• Drug chemistry: The chemical structure of each PDE4 inhibitor is unique. Crisaborole is the most dissimilar to cAMP and contains a boron atom (Figure 1).
• Binding location: Each inhibitor binds approximately to the same enzymatic active site in PDE4; however, there are key differences between the three in how they are bound (or coordinated) in that active site, which impacts drug potency and function.
• cAMP binding in active site: PDE4 binds cAMP in its active site using three major anchor points: (i) a metal site with two divalent metal cations (zinc and/or magnesium); (ii) a conserved glutamine residue; and (iii) a structured water molecule linking and stabilizing the two ends of cAMP through a hydrogen bond network (Figure 1).
• Drug binding in active site: Roflumilast most closely mimics the manner in which cAMP is bound by PDE4, preserving all three major contact points in PDE4 (metal ion site, conserved glutamine, and water molecule/hydrogen bond network) (Figure 1). Apremilast binds in a manner that utilizes the metal ion and glutamine contact points but does not preserve the binding to the critical water residue. Moreover, apremilast unexpectedly possesses an ~90° bend in the molecule, projecting one of its ring moieties (the isoindoyl ring) into a small hydrophobic pocket and away from the catalytic site. Crisaborole, through its boron atom, binds the metal ion site, but fails to bind either the conserved glutamine or central structured water molecule. These differences can be remembered as the “3-2-1” contact point rule for PDE4 inhibitor binding (Figure 1).

Why Some PDE4 Inhibitors Are More Potent and Selective

Structural contact points correlate with binding affinity (IC₅₀). It follows logically from the “3-2-1” rule described above that roflumilast binds to PDE4 the strongest, with 0.7nM (0.0007μM) half-maximal inhibitory concentration (IC₅₀). The next strongest binding is by apremilast, with 0.14μM IC₅₀. This is 200-fold weaker inhibition of PDE4 than roflumilast; apremilast’s binding strength is reduced because of the “kink” or bend in the molecule in PDE4, and this may limit apremilast’s clinical effectiveness. The weakest binding of PDE4 is by crisaborole, with 0.75μM IC₅₀. This is 1,071-fold weaker inhibition of PDE4 than roflumilast (Figure 1).

PDE selectivity. There are 11 major classes of PDE enzymes, with the most relevant to dermatologic disease being PDE4B and PDE4D. A beneficial characteristic of roflumilast is its high selectivity for PDE4B/D, and not the other PDE classes. A closely related compound, piclamilast, inhibits PDE4 more potently (IC₅₀=0.024nM) than roflumilast, but at the cost of reduced selectivity via increased inhibition of PDE1/2/3/5/7/10/11. The only chemical structure differences between roflumilast and piclamilast are the substitution of the chemical groups in positions 3 and 4 on the benzamide core phenyl ring, suggesting those positions may regulate PDE selectivity.

Clinical Implications

Drug selection. The insights provided here inform clinicians that each PDE4 inhibitor used in dermatology is chemically and functionally distinct. The differences in binding of the inhibitors matter for drug potency and inform clinicians that certain PDE4 inhibitors may be preferred for patients with inflammatory dermatoses, such as topical roflumilast over topical crisaborole. We note that oral apremilast is the only dermatologic PDE4 inhibitor that is FDA-approved for psoriatic arthritis, reinforcing the role of PDE4 inhibition in inflammatory pathways.⁵

Drug formulation. In clinical dermatology practice, roflumilast and crisaborole are used in topical formulations, whereas apremilast is an oral drug. Roflumilast is formulated for pediatric and adult patients as either a 0.3% (plaque psoriasis) or 0.15% (atopic dermatitis) cream (and 0.05% cream being developed for pediatric atopic dermatitis), or a 0.3% foam (seborrheic dermatitis and plaque psoriasis), for once-daily use. Crisaborole is formulated as a 2% ointment for twice-daily use in patients with atopic dermatitis. Apremilast is an oral tablet that comes in 10mg, 20mg, or 30mg strengths; the maintenance dose is 30mg twice daily. Apremilast is indicated for patients with plaque psoriasis ages 6 years and older, and adult patients with psoriatic arthritis.

Drug safety and tolerability. PDE4 inhibitors as a class are considered safe drugs. The higher the potency of a PDE4 inhibitor, the greater the risk of gastrointestinal (GI) adverse events (AEs), including nausea, vomiting, and diarrhea; however, these events are dependent on the route of administration. Oral PDE4 inhibitors like apremilast possess a greater risk for these systemic side effects compared to highly potent topical PDE4 inhibitors like roflumilast. This difference is likely due to the unique pharmacokinetic properties of topical roflumilast compared to oral roflumilast. For example, the enhanced safety may relate to the ability for topical roflumilast to be retained in the stratum corneum due to its lipophilic and water-insoluble nature, and its high protein binding affinity, limiting systemic absorption.⁷ In some patients, GI AEs are observed with topical PDE4 inhibitor use. Headache may also be experienced among patients using PDE4 inhibitors. Whereas burning, stinging, and pruritus were problematic with crisaborole ointment application, the cream and foam formulations of roflumilast demonstrate high patient tolerability.^3,8 This tolerability likely stems from a formulation at acidic pH (~5.5) that is non-ceramide stripping and avoids propylene glycol, polyethylene glycol, isopropyl alcohol, ethanol, formaldehyde, formaldehyde-releasing agents, gluten, and fragrances.

Oral versus topical. The oral formulation of roflumilast is converted to an N-oxide derivative during first-pass gut and hepatic metabolism primarily by CYP3A4 and CYP1A2.⁷ This N-oxide derivative has poor bioavailability in the skin, making it less effective than topically delivered roflumilast for inflammatory skin disorders.⁷ The clinical effects of topical roflumilast may not be “improved upon” by just switching to oral roflumilast. Orismilast, a newer selective PDE4B/D inhibitor in development and undergoing clinical trials as an oral therapy for several inflammatory dermatoses (psoriasis, atopic dermatitis, hidradenitis suppurativa), mimics the N-oxide derivative of roflumilast. It has IC₅₀ ~3-10nM for PDE4B and PDE4D, which is stronger binding than apremilast.^9,10 Topical PDE4 inhibitors may be used safely in combination with biologic therapies, and for many patients more effectively and safely than topical corticosteroids, without the need to consider cutaneous and systemic side effects based on area of application or long-term use (Figure 2).

Non-dermatologic patient benefits.Systemic PDE4 inhibition may have a cardioprotective effect in psoriasis and an anti-atherosclerotic effect on monocytes.¹¹ Oral PDE4 inhibition with apremilast is FDA-approved for psoriatic arthritis, providing an alternative for patients with mild to moderate disease who are not candidates for biologic therapy.⁴ PDE4 inhibition may augment GLP-1 signaling via elevated cAMP levels, leading to weight loss on par with oral semaglutide.^12,13

Mechanism of action. PDE4 functions as a upstream central regulator of skin inflammation, and its inhibition can reduce pro-inflammatory cytokines in the Th1, Th2, Th22, and Th17 immune pathways. PDE4 inhibition may increase anti-inflammatory cytokines, such as IL-10.¹⁴ PDE4 inhibition can also correct dysregulated genes involved in maintaining skin barrier integrity. Increased cAMP by PDE4 inhibition has been shown to result in decreased sensory neuron activation which mediates the itch sensation.¹⁵ cAMP is critical for the functioning of regulatory T cells (Tregs), which function as inflammation suppressors in many disease states.^16–18 Treg functioning requires higher cAMP levels than conventional T cells. It remains to be determined whether PDE4 inhibition via small molecules enhances Treg activity.

Conclusion

Structural properties of PDE4 inhibitors, such as chemical composition, binding location, coordination chemistry inside PDE4 active site, and binding affinity are important determinants of their clinical efficacy whether administered topically or orally. Other properties, such as route of administration and drug formulation, impact PDE4 safety and how patients may experience AEs. These insights enable clinicians to make better evidenced-based medical decisions, optimizing therapeutic strategies to elevate patient care.

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