Treatment of Skin Inflammation with Benzoxaborole Phosphodiesterase Inhibitors: Selectivity, Cellular Activity, and Effect on Cytokines Associated with Skin Inflammation and Skin Architecture Changes

Abstract

Psoriasis and atopic dermatitis are skin diseases affecting millions of patients. Here, we characterize benzoxaborole phosphodiesterase (PDE)-4 inhibitors, a new topical class that has demonstrated therapeutic benefit for psoriasis and atopic dermatitis in phase 2 or phase 3 studies.are potent PDE4 inhibitors with similar affinity for PDE4 isoforms and equivalent inhibition on the catalytic domain and the full-length enzyme. These benzoxaboroles are less active on other PDE isozymes. Compd4 binds to the catalytic domain of PDE4B2 with the oxaborole group chelating the catalytic bimetal and overlapping with the phosphate in cAMP during substrate hydrolysis, and the interaction extends into the adenine pocket. In cell culture, benzoxaborole PDE4 inhibitors suppress the release of tumor necrosis factor-a, interleukin (IL)-23, IL-17, interferon-g, IL-4, IL-5, IL-13, and IL-22, and these cytokines contribute to the pathologic changes in skin structure and barrier functions as well as immune dysregulation in atopic dermatitis and psoriasis. Treatment with compd3 or N 6 ,29-O-dibutyryladenosine 39,59-cyclic monophosphate increases cAMP response element binding protein phosphorylation in human monocytes and decreases extracellular signal-regulated kinase phosphorylation in human T cells; these changes lead to reduced cytokine production and are among the mechanisms by which compd3 blocks cytokine release. Topical compd3 penetrates the skin and suppresses phorbol myristate acetate-induced IL-13, IL-22, IL-17F, and IL-23 transcription and calcipotriol-induced thymic stromal lymphopoietin expression in mouse skin. Skin thinning is a major dose-limiting side effect of glucocorticoids. By contrast, repeated application of compd3 did not thin mouse skin. These findings show the potential benefits and safety of benzoxaborole PDE4 inhibitors for the treatment of psoriasis and atopic dermatitis.

Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial

“…84 PDE4 antagonism inhibits production of many inflammatory mediators, including T H 1related (IFN-g), T H 2-related (IL-5), and T H 17-related (IL-8) products in model systems. 15,48,51,[81][82][83][85][86][87][88] In patients with psoriasis treated with the systemic PDE4 inhibitor apremilast, the greatest molecular inhibition is observed for T H 17/T H 22 pathway genes (IL17, IL22, and IL23). 42,51,80,[89][90][91][92][93] T H 17/T H 22centered suppression was also observed in AD lesions in patients treated with 40 mg of apremilast.…”

Crisaborole and Apremilast: PDE4 Inhibitors with Similar Mechanism of Action, Different Indications for Management of Inflammatory Skin Conditions

“…The catalytic domain of PDE4 has been extensively studied and x-ray crystal structures reveal details of the active site that enabled the design of family-specific inhibitors [10] [11].…”

“…• X-ray crystal structures of the catalytic domain of PDE4 isozymes make the design of small molecule inhibitors feasible [11] [32]. • Experimental and clinical evidence have demonstrated that increases in intracellular levels of cAMP will lead to inhibition of formation of multiple mediators of inflammation in several cell types known to be responsible for these inflammatory skin conditions [33].…”

“…as did apremilast (IC 50 range: 8.9 -48 nM). Therefore, both inhibitors are not selective for subtypes of PDE4 [11]. In studies designed to correlate the inhibi-…”

Therapeutic Antibody‐Based Drugs in the Treatment of Human Inflammatory Disorders

“…For example, a small molecule phosphodiesterase-4 inhibitor (apremilast) works by preventing cAMP activation in immune cells, thereby limiting pro-inflammatory cytokine production [42][43][44][45]. It should be noted, however, that initial clinical trials were discontinued due to unexpected side effects such as diarrhoea, headache and nausea, although careful re-examination of dosing regiments and/or new molecular modifications may still be possible.…”