an2728 and Psoriasis

Psoriasis is a chronic immune-mediated skin disease with a significant impact on patients' quality of life. Mild-to-moderate forms of the disease usually require long-term topical treatment, but prolonged use of corticosteroids and vitamin D analogues is limited by adverse effects. With further understanding of psoriasis pathogenesis, new molecules are emerging aiming to fulfil these clinical needs. Tapinarof, an aryl hydrocarbon receptor modulator, has completed a phase III study and demonstrated good efficacy results, even in long treatment courses, with a favourable safety profile. It additionally appears to have a promising remitting effect as patients presented with an average relapsing time of over 3 months. Roflumilast, a phosphodiesterase type 4 inhibitor, also underwent a phase III study with significant lesion improvement and notable pruritus management, and with no reported side effects. Roflumilast was evaluated as an option for intertriginous areas with good outcomes in a small sample, but larger trials are required. The Janus kinase-signal transducer and activator of transcription pathway has been targeted in recent clinical investigations with promising options, currently with brepocitinib pending phase IIb results. Ongoing preclinical studies involving interleukin-2 inhibition, RNA modulators and amygdalin analogues may lead to forthcoming clinical trials. New topical drugs are successfully emerging and future research comparing them to classical options will dictate their clinical role in the treatment of psoriasis.

Topics: Administration, Topical; Aminopyridines; Amygdalin; Benzamides; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclopropanes; Dermatologic Agents; Humans; Interleukin-2; MicroRNAs; Nitriles; Phosphodiesterase 4 Inhibitors; Piperidines; Psoriasis; Pyrazoles; Pyrimidines; Resorcinols; Stilbenes

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Drug Design; Eczema; Humans; Onychomycosis; Psoriasis; Skin Diseases; Treatment Outcome

Phosphodiesterase inhibitors are commonly used drugs. Specific phosphodiesterase inhibitors with anti-inflammatory properties are being assessed as dermatological treatments.. To describe important aspects of phosphodiesterase inhibition and the safety and efficacy of 2 phosphodiesterase- 4 inhibitors being studied for the treatment of dermatologic diseases. We did a non-systematic analysis of literature on phosphodiesterase inhibition followed by a review of published information on apremilast and topical AN2728 and their use for psoriasis and atopic dermatitis.. Apremilast and topical AN2728 have modest efficacy in treatment of psoriasis. Apremilast achieved PASI-75 scores ranging from 24-33%. In phase 2 studies, AN2728 had modest efficacy for psoriasis (40% of patients achieved a ≥ 2 grade improvement as assessed by the Overall target Plaque Severity Score). In phase 2 studies of AN2728 use in atopic dermatitis, subjects achieved a 71% improvement from baseline Atopic Dermatitis Severity Index. In all studies, most adverse effects were minimal. The limitations of this paper are the limited number of published studies, the lack of long-term data, and the lack of head -to - head trials directly comparing phosphodiesterase inhibitors with other treatments.. Phosphodiesterase inhibitors constitute a widely used class of drugs that may see growing use for inflammatory dermatologic diseases.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclic AMP; Dermatitis, Atopic; Humans; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Psoriasis; Thalidomide; Tissue Distribution

Cytokines are signaling molecules that are believed to be key factors in perpetuating the inflammatory process in psoriasis and atopic dermatitis. AN-2728, being developed by Anacor Pharmaceuticals Inc, is a topically administered, boron-containing, anti-inflammatory compound that inhibits PDE4 activity and thereby suppresses the release of TNFalpha, IL-12, IL-23 and other cytokines. At the time of publication, three phase Ib clinical trials, a IIa trial and a IIb trial of AN-2728 in patients with psoriasis had been completed; the compound was also undergoing phase II development for atopic dermatitis, but no data were available for this indication. AN-2728 was reported to be well tolerated and to demonstrate significant effects on markers of efficacy, with results that were comparable to positive controls. AN-2728 appears to have good therapeutic potential, although further and larger trials are required to assess the long-term safety and characterize the broad utility of this drug.

Topics: Animals; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Cytokines; Dermatitis, Atopic; Humans; Inflammation; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Psoriasis

Transcription factor retinoic acid-related orphan receptor 2 (RORC2/RORγT) mediates interleukin (IL)-17A and IL-17F expression. IL-17A plays a central role in the pathogenesis of several inflammatory disorders, including psoriasis. The RORC2 inhibitor PF-06763809 has been hypothesized to inhibit IL-17A production in T-helper 17 (Th17) cells, thereby reducing psoriasis symptoms.. To assess the safety, tolerability and effect on skin infiltrate thickness of PF-06763809 in participants with mild/moderate chronic plaque psoriasis.. This was a randomized, double-blind, first-in-human study (trial registration: ClinicalTrials.gov NCT03469336). Participants received each of the following six treatments once daily for 18 days: three topical doses (2.3%, 0.8%, 0.23%) of PF-06763809, a vehicle and two active comparators (betamethasone and calcipotriol). Primary endpoints included change from baseline in psoriatic skin infiltrate thickness [echo-poor band (EPB) on ultrasonography] at Day 19, and safety. Change in psoriasis-associated gene expression (Day 19), evaluated by real-time reverse transcription PCR of skin biopsies, was an exploratory endpoint.. In total, 17 participants completed the study. Change from baseline in the EPB on Day 19 for all three doses of PF-06763809 was not significantly different from that of vehicle (P > 0.05). A significant reduction in EPB from baseline was observed with betamethasone on Day 19 relative to all other treatments (P < 0.0001). Treatment-related adverse events were mild/moderate. There were no significant differences in gene expression on Day 19 between vehicle and PF-06763809-treated skin lesions.. Using a psoriasis plaque test design, PF-06763809 was found to be well tolerated with an acceptable safety profile in participants with psoriasis, but without reduction in skin infiltrate thickness or disease biomarkers.

Topics: Administration, Topical; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Double-Blind Method; Gene Expression; Humans; Interleukin-17; Male; Middle Aged; Nuclear Receptor Subfamily 1, Group F, Member 3; Organic Chemicals; Psoriasis; Real-Time Polymerase Chain Reaction; Skin; Treatment Failure

Psoriasis of the intertriginous, anogenital, and facial regions remains a therapeutic challenge, with current algorithms lacking a topical agent that exhibits both high efficacy and minimal side effects.. To assess the safety and efficacy of crisaborole 2% ointment-a nonsteroidal phosphodiesterase 4 inhibitor-in the treatment of intertriginous, anogenital, and facial psoriasis.. A double-blind, randomized, vehicle-controlled trial was conducted in 21 participants. Participants were randomized 2:1 to receive 4 weeks of twice-daily treatment with either crisaborole 2% ointment (n = 14) or vehicle ointment (n = 7), followed by 4 weeks of open-label treatment with crisaborole 2% ointment. Disease severity was measured by using the Target Lesion Severity Scale (TLSS).. After 4 weeks, participants in the crisaborole group demonstrated 66% improvement compared with 9% in the vehicle group (P = .0011). Participants in the crisaborole group continued to experience improvement through the open-label phase, demonstrating 81% lesional improvement by week 8, with 71% of these participants achieving clinical clearance. There were no adverse events.. The study was limited to a single tertiary care center and small sample size.. Treatment with crisaborole 2% ointment was well-tolerated and led to clinical improvement in participants with intertriginous, anogenital, or facial psoriasis.

Topics: Adult; Aged; Aged, 80 and over; Anal Canal; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Double-Blind Method; Facial Dermatoses; Female; Genitalia; Humans; Male; Middle Aged; Ointments; Pharmaceutical Vehicles; Psoriasis; Treatment Outcome

Phosphodiesterase 4 (PDE4) is highly expressed in keratinocytes and immune cells and promotes pro-inflammatory responses upon activation. The activity of PDE4 has been attributed to various inflammatory conditions, leading to the development and approval of PDE4 inhibitors as host-directed therapeutics in humans. For example, the topical PDE4 inhibitor, crisaborole, is approved for the treatment of mild-to-moderate atopic dermatitis and has shown efficacy in patients with psoriasis. However, the role of crisaborole in regulating the immunopathogenesis of inflammatory skin diseases and infection is not entirely known. Therefore, we evaluated the effects of crisaborole in multiple mouse models, including psoriasis-like dermatitis, AD-like skin inflammation with and without filaggrin mutations, and Staphylococcus aureus skin infection. We discovered that crisaborole dampens myeloid cells and itch in the skin during psoriasis-like dermatitis. Furthermore, crisaborole was effective in reducing skin inflammation in the context of filaggrin deficiency. Importantly, crisaborole reduced S. aureus skin colonization during AD-like skin inflammation. However, crisaborole was not efficacious in treating S. aureus skin infections, even as adjunctive therapy to antibiotics. Taken together, we found that crisaborole reduced itch during psoriasis-like dermatitis and decreased S. aureus skin colonization upon AD-like skin inflammation, which act as additional mechanisms by which crisaborole dampens the immunopathogenesis in mouse models of inflammatory skin diseases. Further examination is warranted to translate these preclinical findings to human disease.

Topics: Animals; Bridged Bicyclo Compounds, Heterocyclic; Cyclic Nucleotide Phosphodiesterases, Type 4; Dermatitis, Atopic; Disease Models, Animal; Filaggrin Proteins; Humans; Inflammation; Mice; Phosphodiesterase 4 Inhibitors; Pruritus; Psoriasis; Staphylococcal Infections; Staphylococcus aureus

Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and phosphodiesterase 4 (PDE4) is an effective target for the treatment of inflammatory diseases such as psoriasis. Toddacoumalone is a natural PDE4 inhibitor with moderate potency and imperfect drug-like properties. To discover novel and potent PDE4 inhibitors with considerable druggability, a series of toddacoumalone derivatives were designed and synthesized, leading to the compound (2

Topics: Administration, Topical; Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Mice; Phosphodiesterase 4 Inhibitors; Psoriasis; Skin

Topics: Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Genitalia; Humans; Ointments; Psoriasis; Treatment Outcome

Topics: Adalimumab; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Humans; Male; Psoriasis

Topics: Aminopyridines; Benzamides; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Cyclic AMP; Cyclopropanes; Down-Regulation; Humans; Inflammation Mediators; Interleukin-18; Interleukin-1alpha; Interleukin-8; Keratinocytes; MAP Kinase Signaling System; Phosphodiesterase 4 Inhibitors; Psoriasis; Thalidomide; Tumor Necrosis Factor-alpha

Crisaborole, a topical phosphodiesterase-4 (PDE4) inhibitor, is effective in patients with atopic dermatitis. As systemic PDE4 inhibition has also been used with success in psoriasis, clinical trials are underway to determine the utility of topical PDE4 inhibitors in these patients. However, there is no current literature documenting use of crisaborole for psoriasis. Here, we present two cases in which patients with psoriasis were treated successfully with crisaborole.

Topics: Aged; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Female; Humans; Middle Aged; Phosphodiesterase 4 Inhibitors; Psoriasis

Topics: Anti-Inflammatory Agents, Non-Steroidal; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Female; Foot Dermatoses; Hand Dermatoses; Humans; Middle Aged; Psoriasis; Retreatment

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. Crisaborole [AN2728, 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile], compd2 [2-ethoxy-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)nicotinonitrile], compd3 [6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-(2-isopropoxyethoxy)nicotinonitrile], and compd4 [5-chloro-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-((4-oxopentyl)oxy)nicotinonitrile] 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-α, interleukin (IL)-23, IL-17, interferon-γ, 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),2'-O-dibutyryladenosine 3',5'-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.

Topics: Administration, Topical; Animals; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Catalytic Domain; Cyclic AMP Response Element-Binding Protein; Cyclic Nucleotide Phosphodiesterases, Type 4; Cytokines; Dermatitis, Atopic; Female; Gene Expression Regulation; Leukocytes; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Models, Molecular; Phosphodiesterase 4 Inhibitors; Phosphorylation; Psoriasis; Skin; Thymic Stromal Lymphopoietin

A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis.

Topics: Administration, Topical; Animals; Anti-Inflammatory Agents, Non-Steroidal; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Dermatologic Agents; Edema; Humans; Mice; Psoriasis; Structure-Activity Relationship; U937 Cells