Antipsoriatic Drug Research Articles

Industrial Synthesis of Maxacalcitol, the Antihyperparathyroidism and Antipsoriatic Vitamin D3 Analogue Exhibiting Low Calcemic Activity

Maxacalcitol, the 22-oxa-derivative of 1α,25-dihydroxyvitamin D3 and used currently as an antihyperparathyroidism and antipsoriatic drug, has been synthesized in seven chemical steps from 1α-hydroxydehydroepiandrosterone on the basis of our previously developed route. The present synthesis allows the production of the protected form of the penultimate intermediate in 26% overall yield in a kilogram scale reaction employing neither difficult reaction conditions nor chromatographic purification, having overcome all the difficulties involved in the previous route.

Cannabinoids, loratadine and allopurinol as novel additions to the antipsoriatic ammunition

As the current antipsoriatic medications are commonly associated with deleterious side-effects, a determined search for safer agents, which could be used alone or in combination with current antipsoriatic drugs, would be very imperative. Psoriasis is believed to be characterized by a type 1 cytokine pattern; interferon-gamma, interleukin (IL)-2 and tumour necrosis factor (TNF)-alpha are predominantly expressed in this disorder. Nitric oxide, reactive oxygen species, histamine, leukotriene B4, and decreased [corrected] keratinocyte cyclic adenosine monophosphate/cyclic guanosine monophosphate (cAMP/cGMP) ratio are supposed to play roles in the pathogenesis of this disorder. Based on the immunopathogenesis of psoriasis, this paper introduces three novel, potential treatments for this clinical conundrum: (i) cannabinoids, which exert inhibitory effects on antigen processing and macrophage/T-cell interaction and also on the release of IL-2, TNF-alpha and nitric oxide from immune cells; (ii) loratadine, which is an antihistamine capable of increasing [corrected] the cAMP/cGMP ratio and the production of leukotriene B4; and (iii) allopurinol, which scavenges free radicals, inhibits the production of TNF-alpha, and downregulates the expression of intercellular adhesion molecule-1 and P2X7 receptors on monocytes/macrophages, which are involved in antigen presentation and production of the inflammatory response, respectively. Importantly, allopurinol, especially in combination with cyclosporin, has been shown to be effective against experimental autoimmune uveitis, which, like psoriasis, is a cell-mediated autoimmune disorder.

The antipsoriatic drug anthralin accumulates in keratinocyte mitochondria, dissipates mitochondrial membrane potential, and induces apoptosis through a pathway dependent on respiratory competent mitochondria

Anthralin is a potent topical drug, inducing clearance of psoriatic plaques. Anthralin disrupts mitochondrial function and structure, but its mechanism of action remains undefined. This study aimed to determine whether anthralin induced keratinocyte apoptosis as well as to investigate molecular mechanisms and the role of mitochondria. We studied human keratinocytes and human 143B rho(0) cells, which lack mitochondrial DNA and a functional respiratory chain. We show that anthralin disrupts mitochondrial membrane potential (DeltaPsim) and causes endogenous cytochrome c release, resulting in the activation of caspase-3 and characteristic morphological changes of apoptosis. Disruption of DeltaPsim and cytochrome c release were independent of mitochondrial permeability transition or caspase activation. Human 143B rho(0) cells were resistant to anthralin-induced cell death, disruption of DeltaPsim, and cytochrome c release compared with the isogenic 143B rho+ cell line. Using the intrinsic fluorescence of anthralin, rapid accumulation within mitochondria was observed independent of DeltaPsim. Using assays that measure individual respiratory chain complexes, we show that anthralin specifically interacts with ubiquinone pool. These data indicate that anthralin induces apoptosis through a novel mitochondrial pathway dependent on oxidative respiration and involving electron transfer with the ubiquinone pool. These studies identify keratinocyte apoptosis as a potentially important mechanism involved in the clearance of psoriasis.

Inhibition of the Nuclear Factor-κB Signaling Pathway by Leflunomide or Triptolide also Inhibits the Anthralin-Induced Inflammatory Response but Does Not Affect Keratinocyte Growth Inhibition

We performed this study to determine the relationship between activation of nuclear factor (NF)-kappaB and inhibition of keratinocyte growth by anthralin, which not only might be useful for a better understanding of the role of NF-kappaB in the pathogenesis of psoriasis, but also indicate whether the inflammatory reaction induced by anthralin is inseparable from its antipsoriatic activity. The involvement of NF-kappaB was assessed using the antipsoriatic drugs leflunomide and triptolide (T0) as effectors, since they can inhibit NF-kappaB activation induced by anthralin. The results showed that the inhibition of keratinocyte growth by anthralin was not related to the activation of NF-kappaB. Using sodium salicylate, a known NF-kappaB inhibitor, further confirmed this conclusion. Thus it might be possible to inhibit the inflammatory response induced by anthralin via repression of NF-kappaB activation. We found that leflunomide or T0 could significantly inhibit the mRNA overexpression of interleukin-8 and intercellular adhesion molecule-1 in keratinocytes induced by anthralin. Taken together, our data indicate that the growth inhibition of anthralin is related to the NF-kappaB-independent signaling pathway, and that leflunomide or T0 could control proinflammatory cytokine expression induced by anthralin via inhibiting the activation of NF-kappaB.

The use of ciclosporin in psoriasis

Ciclosporin is a cyclic undecapeptide discovered in the 1970s to possess a potent inhibitory action on T lymphocytes. The subsequent discovery, in 1979, that it was remarkably effective in treatment of psoriasis transformed thinking about the nature of the disease, which subsequently became generally recognized as autoimmune in nature. Ciclosporin remains one of the most effective and rapidly acting treatments currently available for psoriasis. Virtually all the diverse manifestations of this disease can respond. The main side effects are nephrotoxicity and hypertension. There is considerable variation between individuals in susceptibility to these so careful monitoring is required. Ciclosporin should be used in single or intermittent short courses for all except the most severe cases as this is safer than continuous treatment. The rate of improvement depends very much on the dose, which ranges from 2 to 5.0 mg/kg/day. Ciclosporin can be combined with any topical treatment and a useful dose‐sparing effect can be achieved in this way if patients are compliant. In severe cases ciclosporin is often used in combination with other systemic antipsoriatic drugs in order to spare the dose of each agent and reduce toxicity. Concurrent or intercurrent use of ultraviolet therapy is discouraged due to the increased risk of non‐melanoma skin cancer. This article reviews the mode of action, pharmacokinetics, indications, contraindications, side effects, dosage regimens, pretreatment screening and monitoring, drug interactions, and use of treatment combinations with ciclosporin in the management of psoriasis.

Interferon-γ-Dependent in vitro Model for the Putative Keratin 17 Autoimmune Loop in Psoriasis: Exploration of Pharmaco- and Gene-Therapeutic Effects

In 1999, A.S. Gudmundsdottir et al. have envisaged an epitope on keratin 17 (K17) as a putative psoriasis major autoantigen recognized by T cells. In a HaCaT keratinocyte model, we now demonstrate that IFN-γ and to a less extent also TNF-α and TGF-α are able to induce K17 protein expression, in contrast to IL-1α, IL-1β, IL-6, IL-8 and IL-18. This supports our hypothesis of an existing proinflammatory cytokine/K17 autoimmune loop as a presumptive positive feedback mechanism driving psoriasis etiopathogenesis. K17 overexpression was now found to also coincide with suppression of keratinocyte proliferation, e.g. induced by NF-kappa B inhibitors (Bay 11-7082 and Bay 11-7085), and thereby correlated hyperapoptosis to be encountered in psoriatic epidermis. Acitretin as an established antipsoriatic drug and the tyrosine kinase inhibitor imatinib decreased, whereas hydrocortisone as well as dexamethasone increased the IFN-γ-induced K17 overexpression. The latter might be another mechanism explaining the well-known rebound phenomena after abrupt withdrawal of corticosteroids in psoriasis treatment. Finally, we defined a K17-directed and effective antisense oligodesoxynucleotide which may hold promise for future gene-therapeutic approaches in psoriasis.

C-25 hydroxylation of 1α,24( R)-dihydroxyvitamin D 3 is catalyzed by 25-hydroxyvitamin D 3-24-hydroxylase (CYP24A1): metabolism studies with human keratinocytes and rat recombinant CYP24A1

Recently, 25-hydroxyvitamin D 3-24-hydroxylase (CYP24A1) has been shown to catalyze not only hydroxylation at C-24 but also hydroxylations at C-23 and C-26 of the secosteroid hormone 1α, 25-dihydroxyvitamin D 3 (1α,25(OH) 2D 3). It remains to be determined whether CYP24A1 has the ability to hydroxylate vitamin D 3 compounds at C-25. 1α,24( R)-dihydroxyvitamin D 3 (1α,24( R)(OH) 2D 3) is a non-25-hydroxylated synthetic vitamin D 3 analog that is presently being used as an antipsoriatic drug. In the present study, we investigated the metabolism of 1α,24( R)(OH) 2D 3 in human keratinocytes in order to examine the ability of CYP24A1 to hydroxylate 1α,24( R)(OH) 2D 3 at C-25. The results indicated that keratinocytes metabolize 1α,24( R)(OH) 2D 3 into several previously known both 25-hydroxylated and non-25-hydroxylated metabolites along with two new metabolites, namely 1α,23,24(OH) 3D 3 and 1α,24(OH) 2-23-oxo-D 3. Production of the metabolites including the 25-hydroxylated ones was detectable only when CYP24A1 activity was induced in keratinocytes 1α,25(OH) 2D 3. This finding provided indirect evidence to indicate that CYP24A1 catalyzes C-25 hydroxylation of 1α,24( R)(OH) 2D 3. The final proof for this finding was obtained through our metabolism studies using highly purified recombinant rat CYP24A1 in a reconstituted system. Incubation of this system with 1α,24( R)(OH) 2D 3 resulted in the production of both 25-hydroxylated and non-25-hydroxylated metabolites. Thus, in our present study, we identified CYP24A1 as the main enzyme responsible for the metabolism of 1α,24( R)(OH) 2D 3 in human keratinocytes, and provided unequivocal evidence to indicate that the multicatalytic enzyme CYP24A1 has the ability to hydroxylate 1α,24( R)(OH) 2D 3 at C-25.

Synthesis of 21-nor-22-oxa-1α,25-dihydroxyvitamin D 3 derivatives in quest of a drug with low calcemic activity

Two 21-nor-22-oxa-1α,25-dihydroxyvitamin D 3 derivatives have been synthesized in quest of a drug with lower calcemic activity than Maxacalcitol, 22-oxa-1α,25-dihydroxyvitamin D 3, being used as antihyperparathyroidism and antipsoriatic drug. Of two 21-nor products obtained, the product carrying one carbon elongated side chain with diethylcarbinol moiety has been found to exhibit comparable differentiation-inducing activity to Maxacalcitol with much lower exhibition of calcemic activity.

Antipsoriatic drug anthralin induces EGF receptor phosphorylation in keratinocytes: requirement for H(2)O(2) generation.

Even though anthralin is a well-established topical therapeutic agent for psoriasis, little is known about its effects and biochemical mechanisms of signal transduction. In contrast to a previous report, we found that anthralin induced time- and concentration-dependent phosphorylation of epidermal growth factor receptor in primary human keratinocytes. Four lines of evidence show that this process is mediated by reactive oxygen species. First, we found that anthralin induces time-dependent generation of H(2)O(2). Second, there is a correlation between a time-dependent increase in anthralin-induced epidermal growth factor receptor phosphorylation and H(2)O(2) generation. Third, the structurally different antioxidants n-propyl gallate and N-acetylcysteine inhibited epidermal growth factor receptor phosphorylation induced by anthralin. Fourth, overexpression of catalase inhibited this process. The epidermal growth factor receptor-specific tyrosine kinase inhibitor PD153035 abrogated anthralin-induced epidermal growth factor receptor phosphorylation and activation of extracellular-regulated kinase 1/2. These findings establish the following sequence of events: (1) H(2)O(2) generation, (2) epidermal growth factor receptor phosphorylation, and (3) extracellular-regulated kinase activation. Our data identify anthralin-induced reactive oxygen species and, more specifically, H(2)O(2) as an important upstream mediator required for ligand-independent epidermal growth factor receptor phosphorylation and downstream signaling.

Restoration of hair growth in mice with an alopecia areata-like disease using topical anthralin.

Anthralin is a widely used topical anti-psoriatic drug that may have an immunomodulating effect on alopecia areata (AA) as it does in psoriasis. The aims of the present study were to investigate the effects of anthralin on hair growth in balding C3H/HeJ mice affected by an AA-like disease and to study the underlying mechanisms. Affected C3H/HeJ mice were treated daily for 10 weeks on half of the dorsal skin with 0.2% anthralin and the contra-lateral side was treated with the vehicle ointment. The percentage of surface hair coverage and hair density was graded weekly for both sides and hair growth indices were calculated using these two variables. Hair regrowth was observed in 9/14 mice on the treated sides. Four mice displayed near complete replacement of normal density and length hairs. All the vehicle-treated sides showed either no change or continued hair loss. An RNase protection assay (RPA) showed that expression of tumor necrosis factor-alpha (TNF-alpha) and -beta were inhibited by anthralin upon successful treatment. It appears that anthralin may be an effective therapy for C3H/HeJ mice with AA and certain cytokines may be involved in the therapeutic effects of anthralin on restoring hair regrowth in AA-affected C3H/HeJ mice.

Comparison of Growth-inhibitory Agents by Fluorescence Imaging of Human Skin Re-epithelialization In vitro

Drug screening procedures should preferably utilize experimental settings mimicking the in vivo situation. The aim of this study was to evaluate a skin explant model as a tool to identify topical agents with anti-proliferative properties in human epidermis. Re-epithelialization was initiated from a skin punch biopsy explanted onto de-epidermized dermis and cultured at the air-liquid interface in the presence of epidermal growth factor receptor inhibitor PKI166, tacrolimus or established topical anti-psoriatic drugs: betamethasone, calcipotriol, dithranol and tazarotene. Neo-epidermal extension was traced by fluorescence microscopy prior to histomorphometric analysis. PKI166 at 1 microM decreased the mean radial outgrowth rate (-19%), frequency of BrdU-positive (-37%) and laminin 5-positive (-45%) cells, indicating reduced proliferation and migration of neo-epidermal keratinocytes. However, the papillomatosis index and epithelial thickness were not significantly affected. Calcipotriol at 1 microM had a similar effect on the outgrowth rate (-15%) and fraction of laminin 5-stained keratinocytes (-40%). Furthermore, calcipotriol significantly reduced mean neo-epidermal thickness. Equimolar concentrations of the other test compounds had no apparent effect on histology or outgrowth parameters. This study exemplifies the versatility of combined dynamic and morphological analysis and emphasizes the potential of epidermal growth factor receptor-directed inhibition in hyperproliferative disorders of the epidermis.

Effect of Topical PPARβ/δ and PPARγ Agonists on Plaque Psoriasis

Background: Ligands of nuclear hormone receptors such as glucocorticoid, retinoid and vitamin D are useful antipsoriatic drugs. Peroxisome proliferator-activated receptors (PPARs), which also belong to the nuclear hormone receptor superfamily, are pleiotropic regulators of growth and differentiation in many cell types, including the keratinocytes. Recent reports have dealt with the involvement of PPARα in epidermal processes such as barrier development, proliferation and differentiation. In a pilot study of topical clofibrate, a PPARα ligand, we did not find any antipsoriatic activity. No study on the effect of topical application of other PPAR subtype ligands (PPARβ/δ and γ) has been published. Objectives: The purpose of this pilot study is to explore the clinical efficacy of the topical application of potent PPARβ/δ and γ agonists on plaque psoriasis, tetradecylthioacetic acid (TTA) and rosiglitazone, respectively. Methods: In a pilot study on psoriatic patients, 8 individuals (5 male/3 female) were treated twice daily for 30 days with vehicle (n = 14 plaques), rosiglitazone 0.5% (n = 18) and TTA 0.5% (n = 18). Assessments of the PASI plaque score were carried out on days 0, 4, 7, 11, 14 and 30. Results: No statistically significant difference was found at any of the examination times, between vehicle, rosiglitazone and TTA in terms of reduction of the PASI plaque score for total, scale and infiltration scores. Treatments were well tolerated, and skin irritation, adverse drug-related symptoms and dropouts did not occur. Conclusions: With the reservations due to the limited nature of this pilot trial, it seems that these topical PPARβ/δ and γ agonists do not exert a strong antipsoriatic effect when used alone at 0.5%.

Comparison of antiproliferative effects of experimental and established antipsoriatic drugs on human keratinocytes, using a simple 96-well plate assay

Comparison of antiproliferative effects of experimental and established antipsoriatic drugs on human keratinocytes, using a simple 96-well plate assay

The Potential of the Essential Fatty Acid-Deficient Hairless Rat as a Psoriasis Screening Model for Topical Anti-Proliferative Drugs

The objective of this study was to establish essential fatty acid deficiency (EFAD) in hairless rats and investigate the potential of this model as a psoriasis screening model by testing the effects of calcipotriol and dithranol on differentiation and proliferation in the epidermis. Hairless rats were fed with a fat-free diet lacking linoleic acid. The EFAD condition was established within 8 weeks. In order to ensure that this condition had been established, several parameters were measured and observed, i.e. animal weight, water consumption, transepidermal water loss, clinical skin symptoms, histology of the epidermis and fatty acid analysis of serum and skin. Immediately after the EFAD condition had been established, the animals were treated with dithranol ointment or different concentrations of calcipotriol solution. A reduction in epidermal thickness of 15–20% was seen after the treatment with calcipotriol. Dithranol and its coal tar-containing vehicle also showed a reductive effect on epidermal thickness. EFAD hairless rats possess various histological changes resembling psoriasis. These histological changes normalise during treatment with anti-psoriatic drugs as calcipotriol, dithranol and coal tar. The results of the present study indicate that the EFAD rat may be a useful model for studies of anti-psoriatic drugs affecting cell proliferation.

A Simple Technique for High-Throughput Screening of Drugs That Modulate Normal and Psoriasis-Like Differentiation in Cultured Human Keratinocytes

Established treatments for psoriasis act ei-ther on hyperproliferation, inflammation, aberrant epidermal differentiation or a combination of these aspects of the disease. Potential new drugs for treatment of psoriasis or other disorders with abnormalities in epidermal differentiation can be identified by high-throughput screening of large compound libraries using surrogate markers for the disease. Here we describe a screening model to detect pharmacologically active drugs in two keratinocyte-based, 96-well culture models that use expression of cytokeratin 10 (CK10) and skin-derived antileucoprotease (SKALP)/elafin as markers for normal and psoriatic differentiation, respectively, and allow multiple parameters to be determined from a single well. In this model we tested a number of compounds in a pharmacological range from 10^–7 to 10^–5 M, including known antipsoriatic drugs, and experimental drugs that are potentially useful in the treatment of psoriasis. All-trans-retinoic acid, dithranol and the p38 mitogen-activated protein (MAP) kinase inhibitor SB220025 displayed a strong inhibitory effect on SKALP expression while cyclosporin A, dexamethasone, the vitamin D₃ derivative calcipotriol and the p38 MAP kinase inhibitor SB203580 showed only moderate inhibition. Methotrexate and dimethylfumarate did not affect the expression of SKALP. With respect to CK10 expression, all-trans-retinoic acid, calcipotriol, SB203580 and SB220025 exhibited strong inhibition while dithranol showed only moderate suppression of this normal differentiation marker. Expression levels of CK10 were not significantly affected by dexamethasone, methotrexate, cyclosporin A or dimethylfumarate. This model system parallels most, but not all, findings on the in vitro effect of known antipsoriatic drugs on keratinocytes. In addition, the model identifies p38 MAP kinase inhibitors as potent suppressors of differentiation-associated gene expression. Although further delineation and validation of this model is required, we conclude that the system is amenable to down-scaling and application as a high-throughput screen for differentiation-modifying compounds.

Development of a Keratinocyte-Based Screening Model for Antipsoriatic Drugs Using Green Fluorescent Protein Under the Control of an Endogenous Promoter

Inflamed epidermis (psoriasis, wound healing, ultraviolet-irradiated skin) harbors keratinocytes that are hyperproliferative and display an abnormal differentiation program. A distinct feature of this so-called regenerative maturation pathway is the expression of proteins such as the cytokeratins CK6, CK16, and CK17 and the antiinflammatory protein SKALP/elafin. These proteins are absent in normal skin but highly induced in lesional psoriatic skin. Expression of these genes can be used as a surrogate marker for psoriasis in drug-screening procedures of large compound libraries. The aim of this study was to develop a keratinocyte cell line that contained a reporter gene under the control of a psoriasis-associated endogenous promoter and demonstrate its use in an assay suitable for screening. We generated a stably transfected keratinocyte cell line that expresses enhanced green fluorescent protein (EGFP), under the control of a 0.8-kb fragment derived from the promoter of the SKALP/elafin gene, which confers high levels of tissue-specific expression at the mRNA level. Induction of the SKALP promoter by tumor necrosis factor-alpha resulted in increased expression levels of the secreted SKALP-EGFP fusion protein as assessed by direct readout of fluorescence and fluorescence polarization in 96-well cell culture plates. The fold stimulation of the reporter gene was comparable to that of the endogenous SKALP gene as assessed by enzyme-linked immunosorbent assay. Although the dynamic range of the screening system is limited, the small standard deviation yields a Z factor of 0.49. This indicates that the assay is suitable as a high-throughput screen, and provides proof of the concept that a secreted EGFP fusion protein under the control of a physiologically relevant endogenous promoter can be used as a fluorescence-based high-throughput screen for differentiation-modifying or antiinflammatory compounds that act via the keratinocyte.

Effects of fumaric acid esters on differentiation of dendritic cells in vitro

OBJECTIVE: To investigate the effect of anti-psoriatic drug fumaric acid esters (FAE) on the differentiation of dendritic cells (DC). METHODS: Dendritic cells were obtained by differentiating human monocytes in vitro. Flow cytometry was used to analyse the effect of FAE on cell surface expression of CD1a, CD14, CD40, CD80, CD86 and HLA-DR by monocyte-derived dendritic cells (MoDC). Mixed lymphocyte reaction (MLR) was made to demonstrate the influence of FAE on T cell stimulatory activity of MoDC. RESULTS: Dimethylfumarate and methylhydrogenfumarate-calcium-salt (0.01 approximate, equals 100 mg/L) inhibited MoDC differentiation as well as reducing the capacity of MoDC to stimulate lymphocytic proliferation in MLR. CONCLUSION: The mode of action of FAE in pso riasis may be mediated by inhibition of DC differentiation.

Development of a Keratinocyte-Based Screening Model for Antipsoriatic Drugs Using Green Fluorescent Protein Under the Control of an Endogenous Promoter

Development of a Keratinocyte-Based Screening Model for Antipsoriatic Drugs Using Green Fluorescent Protein Under the Control of an Endogenous Promoter

Short-term methotrexate therapy in psoriasis: a study of 197 patients.

Methotrexate (MTX) is one of the most effective antipsoriatic drugs available. Although it is undeniably hepatotoxic, it can be used safely in most patients with severe psoriasis if established guidelines are followed. Current opinion on the monitoring of hepatic damage is divided, however, and the need for repeated liver biopsies during MTX therapy is being re-examined. We have used MTX in a short-term protocol in our patients with psoriasis for the past 20 years, and have recently attempted to minimize or eliminate the need for liver biopsies using this regimen. Data on 244 psoriatics who were given MTX from 1981 to 2000 have been reviewed. Our protocol entailed the use of weekly oral MTX at the full therapeutic dose during episodes of peak disease activity, with tapering off of MTX when the disease subsided in response to treatment combined with natural/seasonal remission. Intensive topical and heliotherapy were encouraged throughout to facilitate the earliest possible drug withdrawal and the longest possible drug-free interval before the next relapse. Strict inclusion criteria were applied before starting MTX. A total of 243 cycles of MTX therapy have been given to 197 evaluable patients. More than 75% improvement occurred in 88% of patients in 8.5 +/- 5.1 weeks. The mean cumulative dose was 709.3 +/- 369.2 mg and the mean duration of follow-up was 16.5 +/- 9.1 months. Fifteen (6.1%) patients had serious adverse effects requiring the cessation of therapy. Only three patients had deranged liver function tests. Thirty-four pre-MTX and 13 post-MTX liver biopsies were taken, which revealed grade I or II changes that were nonprogressive. Our experience with short-term MTX therapy has enabled us to safely administer MTX to our patients with minimal recourse to liver biopsy. In developing countries, where advanced noninvasive methods for the assessment of liver damage are unaffordable or unavailable, this interrupted, short-term regimen may present an acceptable and safe method of using MTX in carefully selected patients with severe psoriasis.

New strategy for antedrug application: development of metalloproteinase inhibitors as antipsoriatic drugs.

Phosphonamide-based inhibitors were synthesized and evaluated for the inhibitory activities against the shedding of epidermal growth factors, amphiregulin and heparin-binding EGF-like growth factor, that would participate in the development of psoriasis. All compounds exhibited excellent inhibitory activities for these EGF sheddings; however, they also inhibited matrix metalloproteinases (MMPs). To avoid adverse effects reported by the clinical development of MMP inhibitors, the antedrug concept was introduced. Among the phosphonamide inhibitors, the 2,2,2-trifluoroethyl ester 8d and 2,2-difluoroethyl ester 8c showed rapid decomposition in human plasma, which is an essential property for the antedrug. Topical applications of these compounds significantly suppressed TPA-induced epidermal hyperplasia in murin skin, a model of psoriasis. These results suggested that the phosphonamide-based inhibitors have a therapeutic potential for the treatment of psoriasis as an antedrug application.