CN114767665A - Use of 5-tetradecyloxy-2-furancarboxylic acid for preparing medicine for treating psoriasis-like dermatitis - Google Patents
Use of 5-tetradecyloxy-2-furancarboxylic acid for preparing medicine for treating psoriasis-like dermatitis Download PDFInfo
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- CN114767665A CN114767665A CN202110653662.9A CN202110653662A CN114767665A CN 114767665 A CN114767665 A CN 114767665A CN 202110653662 A CN202110653662 A CN 202110653662A CN 114767665 A CN114767665 A CN 114767665A
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- dermatitis
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- hydroxy
- hydrogen
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Abstract
The invention provides application of a compound shown in a formula I or a pharmaceutically acceptable salt, a deuteron, a solvate, a metabolite or a prodrug thereof in preparing a medicament for treating psoriasis-like dermatitis, wherein R is1And R2Identical or different and is hydrogen, halogen, hydroxy, C1‑12Alkyl or C1‑12An alkoxy group.
Description
Technical Field
The invention relates to the technical field of medicines, and particularly relates to a medicine for treating psoriasis-like dermatitis and application thereof.
Background
Psoriasis, commonly known as "psoriasis", is classified as a ten persistent ailments in the world by the World Health Organization (WHO). The incidence rate of Chinese psoriasis is 0.3-0.5%, and the number of patients is about 1000 ten thousand, which is on the trend of increasing year by year.
Psoriasis is a common chronic systemic inflammatory disease, mainly affects the skin and joints, seriously affects the physical and mental health of patients and brings heavy economic burden to the society. Psoriasis is a complex, multi-gene affected, immune-mediated disease that is triggered by environmental factors such as infection, medication, trauma, and emotional stress. The immunopathogenesis of psoriasis is centered on differentiation of T lymphocytes regulated by Dendritic Cells (DC), and is dominated by the inflammatory axis mediated by Interleukin (IL) -23/IL-17. Epidermal Langerhans Cells (LC), as the only DC subset in the epidermis, play an important role in the pathogenesis of psoriasis.
Psoriasis is known to be associated with metabolic syndrome, including hypertension, dyslipidemia, insulin resistance, obesity and cardiovascular disease. Lipid disorders involving the circulatory system and the various skin layers are associated with the disease severity of psoriasis. Combined transcriptome analysis also revealed major changes in lipid pathways in psoriatic lesions, suggesting that abnormal lipid metabolism plays a key role in the pathogenesis of psoriasis. However, therapeutic approaches to abnormal lipid metabolism have not been attempted.
There is no treatment for psoriasis and the available treatments have limitations in terms of effectiveness and safety, such as cyclosporin a, steroids, methotrexate and photochemotherapy, which are immunosuppressive, but are not ideal due to side effects.
Therefore, the research on the pathogenesis of psoriasis is further advanced in the field, and the development of a new generation of new drug and a treatment method for treating psoriasis, which have strong targeting property, good long-term curative effect, high safety and low price, is imperative.
Disclosure of Invention
The invention mainly aims to provide a medicament for treating psoriasis-like dermatitis and application thereof, and aims to solve the problems of poor curative effect and more toxic and side effects of common medicaments for treating psoriasis-like dermatitis in the prior art.
In order to achieve the above objects, according to one aspect of the present invention, there is provided a use of a compound represented by the following formula I, or a pharmaceutically acceptable salt, deuteron, solvate, metabolite or prodrug thereof, for the manufacture of a medicament for treating psoriatic dermatitis,
wherein R is1And R2Identical or different and is hydrogen, halogen, hydroxy, C1-12Alkyl or C1-12An alkoxy group.
According to another aspect of the present invention, there is provided a use of a pharmaceutical composition comprising a compound represented by the following formula I, or a pharmaceutically acceptable salt, deuterode, solvate, metabolite or prodrug thereof, in the manufacture of a medicament for the treatment of psoriatic dermatitis,
wherein R is1And R2The same or differentAnd is hydrogen, halogen, hydroxy, C1-12Alkyl or C1-12An alkoxy group.
According to another aspect of the present invention, there is provided the use of a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutically acceptable salt, deuterode, solvate, metabolite or prodrug thereof, in the manufacture of a medicament for the treatment of psoriatic dermatitis,
wherein R is1And R2Identical or different and is hydrogen, halogen, hydroxy, C1-12Alkyl or C1-12An alkoxy group.
Further, the pharmaceutical preparation further comprises pharmaceutically acceptable pharmaceutic adjuvants.
Further, the pharmaceutical preparation is solid tablet, oral liquid, capsule, dripping pill, ointment, gel preparation, transdermal patch, microemulsion or aerosol.
Further, the pharmaceutical preparation is an ointment, a gel preparation, a transdermal patch, a microemulsion preparation or an aerosol.
Further, the pharmaceutic adjuvant comprises one or more of a matrix material, a humectant, a pH regulator, a surfactant, a preservative, a chelating agent and a stabilizer.
Further, the pharmaceutical composition or the pharmaceutical preparation further comprises one or more of methotrexate, tretinoin, cyclosporin a, etanercept, infliximab, adalimumab, and ubenizumab.
Further, R1And R2Identical or different and are hydrogen, hydroxy, C1-6Alkyl or C1-6An alkoxy group;
further, R1And R2Identical or different and hydrogen, hydroxy, methyl or methoxy;
further, the compound is 5-tetradecyloxy-2-furancarboxylic acid.
Further, the compounds treat psoriatic dermatitis by inhibiting epidermal Langerhans cell immune function.
Further, the compounds inhibit epidermal Langerhans cell maturation, antigen phagocytosis and IL-23p19 secretion by down-regulating the neutral lipid level of epidermal Langerhans cells to treat psoriatic dermatitis.
Further, the psoriatic dermatitis is imiquimod-induced psoriatic dermatitis.
The invention has the beneficial effects that:
imiquimod (IMQ) -induced psoriasis-like skin inflammation can be reduced by subcutaneous injection of 5-tetradecyloxy-2-furancarboxylic acid, wherein 5-tetradecyloxy-2-furancarboxylic acid down-regulates the neutral lipid levels of epidermal langerhans cells, inhibiting their maturation, antigen phagocytosis and IL-23p19 secretion.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without exceeding the protection scope of the present application.
FIG. 1 is a schematic diagram showing a chemical structural formula of 5-tetradecyloxy-2-furoic acid (5-tetradecyloxy-2-furoic acid, TOFA).
Figure 2 is a flow chart of an experiment in which TOFA was injected subcutaneously to treat IMQ to induce psoriasis-like skin inflammation.
Fig. 3 is a histopathological picture of IMQ-induced psoriasis-like skin inflammation reduced by subcutaneous TOFA injection.
Figure 4 is a graph of the PASI score for reducing IMQ-induced psoriasis-like skin inflammation with subcutaneous TOFA injection.
FIG. 5 is a graph of experimental results of subcutaneous TOFA injection to reduce IMQ-induced psoriasis-like skin inflammation resulting in skin thickening.
FIG. 6 is a graph showing the trend of IMQ-induced changes in neutral lipid content in epidermal Langerhans cells in mice injected subcutaneously with TOFA.
FIG. 7 is a graph showing the results of flow cytometry (FACS) to downregulate the neutral lipid content of epidermal Langerhans cells by subcutaneous injection of TOFA.
FIG. 8 is a graph showing the flow cytometry (FACS) results of subcutaneous injection of TOFA to down-regulate MHC-II expression in epidermal Langerhans cells.
FIG. 9 is a graph showing the flow cytometry (FACS) results of subcutaneous injection of TOFA to down-regulate the expression of CD80 in epidermal Langerhans cells.
FIG. 10 is a graph showing the results of flow cytometry (FACS) demonstrating the ability of subcutaneous TOFA to inhibit antigen phagocytosis by epidermal Langerhans cells.
FIG. 11 is a graph showing the results of flow cytometry (FACS) demonstrating the ability of subcutaneous injection of TOFA to inhibit IL-23 secretion by epidermal Langerhans cells.
Detailed Description
The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are some, but not all, embodiments of the present application. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
The present invention is described in further detail below with reference to specific examples, which are not to be construed as limiting the scope of the invention as claimed herein.
As described in the background section, the existing medicines for treating the psoriasis-like dermatitis have the problems of poor curative effect and more toxic and side effects. In order to solve the problems, the invention provides application of a compound shown in the formula I or a pharmaceutically acceptable salt, a deuterode, a solvate, a metabolite or a prodrug thereof in preparing a medicament for treating psoriasis-like dermatitis,
wherein R is1And R2Identical or different and is hydrogen, halogen, hydroxy, C1-12Alkyl or C1-12An alkoxy group.
According to another aspect of the present invention, there is provided a use of a pharmaceutical composition comprising a compound represented by the following formula I, or a pharmaceutically acceptable salt, deuterode, solvate, metabolite or prodrug thereof, in the manufacture of a medicament for the treatment of psoriatic dermatitis,
wherein R is1And R2Identical or different and is hydrogen, halogen, hydroxy, C1-12Alkyl or C1-12An alkoxy group.
According to another aspect of the present invention, there is provided the use of a pharmaceutical formulation comprising a compound of formula I, or a pharmaceutically acceptable salt, deuterode, solvate, metabolite or prodrug thereof, in the manufacture of a medicament for the treatment of psoriatic dermatitis,
wherein R is1And R2Identical or different and is hydrogen, halogen, hydroxy, C1-12Alkyl or C1-12An alkoxy group.
As used herein, the phrase "pharmaceutically acceptable salts" includes alkali metal salts, such as sodium, potassium, lithium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as iron salts, copper salts, cobalt salts, etc.; organic base salts such as ammonium salts, triethylamine salts, pyridine salts, picoline salts, 2, 6-lutidine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, cyclohexylamine salts, ethylenediamine salts, guanidine salts, isopropylamine salts, trimethylamine salts, tripropylamine salts, triethanolamine salts, diethanolamine salts, ethanolamine salts, dimethylethanolamine salts, dicyclohexylamine salts, caffeine salts, procaine salts, choline salts, betaine salts, benzamidine penicillin salts, glucamine salts, N-methylglucamine salts, theobromine salts, tromethamine salts, purine salts, piperazine salts, morpholine salts, piperidine salts, N-ethylpiperidine salts, tetramethylamine salts, dibenzylamine salts, phenylglycine alkyl ester salts and the like; hydrohalic acid salts such as hydrofluoride, hydrochloride, hydroiodide, hydrobromide and the like; inorganic acid salts such as hydrochloride, nitrate, sulfate, perchlorate, phosphate and the like; lower alkanesulfonic acid salts such as methanesulfonic acid salt, trifluoromethanesulfonic acid salt, ethanesulfonic acid salt, etc.; arylsulfonates such as benzenesulfonate, p-toluenesulfonate and the like; organic acid salts such as acetate, benzoate, fumarate, formate, trifluoroacetate, furoate, gluconate, glutamate, glycolate, isethionate, lactate, maleate, malate, mandelate, mucate, pamoate, pantothenate, stearate, succinate, sulfonamide, tartrate, malonate, 2-hydroxypropionate, citrate, salicylate, oxalate, glycolate, glucuronate, galacturonate, citrate, lysine, arginine, aspartate, cinnamate and the like.
As used herein, the phrase "deuteron" refers to a deuterium-containing compound formed by the substitution of one or more hydrogens in the group of a compound of formula I with deuterium.
As used herein, the phrase "solvate" refers to a compound of the present invention or a salt thereof, which also includes stoichiometric or non-stoichiometric amounts of solvents bound with intermolecular non-covalent forces. When the solvent is water, it is a hydrate.
As used herein, the phrase "metabolite" refers to the product of a particular compound or salt thereof that is obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, the phrase "prodrug" represents a compound that is converted in vivo to the compound of formula I. Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and can be phenyl ester, aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters.
As used herein, the term "alkyl" refers to a saturated, monovalent, unbranched or branched hydrocarbon chain. Examples of alkyl groups include, but are not limited to: (C)1-C3) Alkyl radicals, such as methyl, ethyl, propyl, isopropyl, and (C)4-C8) Alkyl radicals, such as 2-methyl-l-propyl, 2-methyl-2-propyl, 2-methyl-l-butyl, 3-methyl-l-butyl, 2-methyl-3-butyl, 2-dimethyl-l-butyl, 2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-dimethyl-l-butyl, 3-dimethyl-1-butyl, 2-ethyl-l-butyl, isobutyl, tert-butyl, and the like, Sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, and the like. Any alkyl group may be unsubstituted or substituted with one or more suitable substituents.
As used herein, the term "alkoxy" refers to an oxygen ether group of an alkyl group. Examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, sec-butoxy, tert-butoxy, n-ethoxy and the like. An alkoxy group may be unsubstituted or substituted with one or more suitable substituents.
As used herein, the term "halogen" refers to fluorine, chlorine, bromine or iodine. Accordingly, the term "halo" refers to fluoro, chloro, bromo, and iodo.
In the present invention, the term "treatment" also includes "prevention", unless there is a specific statement to the contrary. The terms "treatment" and "treating" should be construed accordingly.
The medicament, the pharmaceutical composition and the pharmaceutical preparation are used for treating lipid metabolism disorder of psoriasis, directly inhibit inflammation from a metabolic level, and reduce psoriasis-like skin inflammation by inhibiting excessive lipid synthesis.
The invention also provides a method of treating psoriatic dermatitis comprising administering to said patient a therapeutically effective amount of a medicament, pharmaceutical composition and pharmaceutical formulation as defined above.
The amount of drug to achieve successful treatment will of course depend on the patient and the severity of the psoriatic dermatitis. The dosage may be conveniently determined by the skilled pharmacist.
As used herein, the terms "therapeutically effective amount" and "effective amount" mean that the substance or amount of substance is effective to prevent, alleviate or ameliorate one or more symptoms of a disease or disorder, and/or prolong the survival of the subject being treated.
In a preferred embodiment, the pharmaceutical formulation further comprises a pharmaceutically acceptable pharmaceutical excipient.
In a preferred embodiment, the compound of formula I in the pharmaceutical formulation of the present invention is present in a concentration ranging from 1 to 20% by weight of the total composition.
In a preferred embodiment, the compound of formula I in the pharmaceutical formulation of the invention is present in a concentration ranging from 1 to 10% by weight of the total composition.
In a preferred embodiment, the compound of formula I in the pharmaceutical formulation of the present invention is present in a concentration ranging from 2 to 8% by weight of the total composition.
In a preferred embodiment, the pharmaceutical preparation is a solid tablet, an oral liquid, a capsule, a drop pill, an ointment, a gel preparation, a transdermal patch, a microemulsion preparation or an aerosol.
In a preferred embodiment, the pharmaceutical formulation is an ointment, a gel formulation, a transdermal patch, a microemulsion formulation or an aerosol.
In a preferred embodiment, a microemulsion preparation or ointment formulated with conventional excipients for cosmetic preparations, in particular vaseline, liquid paraffin and lanolin, is used.
In a preferred embodiment, the pharmaceutical excipient comprises one or more of a matrix material, a humectant, a pH adjuster, a surfactant, a preservative, a chelating agent, and a stabilizer.
In some embodiments, the matrix material is selected from one or a mixture of at least two of carbomer, croscarmellose sodium, sodium alginate, chitosan, petrolatum, paraffin, beeswax, stearic acid, lanolin, polyethylene glycol, glyceryl monostearate.
In a preferred embodiment, the moisturizer is a substance that moisturizes and softens the skin. The humectant may be selected from glycerin, sorbitol, propylene glycol, polyethylene glycol, and mixtures thereof.
In a preferred embodiment, the pH adjusting agent sets and/or maintains the pH of the composition at a desired value. The pH adjusting agent may be selected from triethanolamine, citric acid, acetic acid, phosphoric acid, propionic acid, lactic acid, carbonic acid, ammonium/ammonia, sodium hydroxide, and mixtures thereof.
In a preferred embodiment, the surfactant is a fatty acid soap, sodium lauryl sulfate, sodium laureth sulfate, sodium cetylpolyoxyethylene ether phosphate, soya lecithin (soya lecithin), primary, secondary and tertiary amines of higher alkyl groups and quaternary ammonium salts such as octadecyl trimethyl ammonium chloride, C12-14One or more of alkyl dimethyl benzyl ammonium chloride, dioctadecyl dimethyl sodium chloride, cocamidopropyl betaine, imidazoline, sorbitan monocinnamate, ethylene oxide addition product, polyoxyethylene lauryl ether, coconut diethanolamide, oleic acid monoglyceride, polyoxyethylene castor oil and polyoxyethylene lanolin.
In a preferred embodiment, the preservative prevents or minimizes deterioration of formulation components due to the presence of different types of microorganisms. The preservative may be selected from the group consisting of phenoxyethanol, tropolone, chlorphenesin, ethylhexylglycerin, isothiazolidone (isothiazolidone), diazolidinyl urea, imidazolidinyl urea, and parabens, and mixtures thereof.
In a preferred embodiment, the chelating agent complexes and neutralizes metal ions that may affect the stability and/or appearance of the pharmaceutical formulation. The chelating agent may be a monoatomic chelating ligand and a polydentate chelating ligand. The chelating agent may be selected from ethylenediaminetetraacetic acid (EDTA), nitrilotriacetic acid (NTA), hydroxyethylethylenediaminetriacetic acid (HEEDTA), diethylenetriaminepentaacetic acid (DTPA), Diethanolglycine (DEG), Ethanoldiglycine (EDG), citric acid, phosphoric acid, tartaric acid, or salts thereof, and mixtures thereof.
In some embodiments, the stabilizer is selected from one or more of disodium edetate, sodium sulfite, and paraben.
The compounds of the invention may be used in combination with other known drugs for the indicated purpose for the treatment of psoriatic dermatitis, which constitutes a further aspect of the invention. In a preferred embodiment, the pharmaceutical composition or the pharmaceutical formulation further comprises one or more of methotrexate, tretinoin, cyclosporin a, etanercept, infliximab, adalimumab, and ubeniumumab.
In a preferred embodiment, R1And R2Identical or different and is hydrogen, hydroxy, C1-6Alkyl or C1-6An alkoxy group;
in a preferred embodiment, R1And R2Identical or different and hydrogen, hydroxy, methyl or methoxy;
in a preferred embodiment, the compound is 5-tetradecyloxy-2-furancarboxylic acid. The chemical structural formula is shown in figure 1.
In a preferred embodiment, the compounds are useful for treating psoriatic dermatitis by inhibiting epidermal langerhans cell immune function.
Among them, Langerhans Cells (LC) are one of the non-keratinocytes of epidermis, and are distributed in the epidermis in a very small amount. Langerhans cells have dendritic processes interspersed among spinous cells. Nuclei are irregular, Golgi complex develops, and lysosomes are abundant. There is also a special small tennis racket-shaped particle, called a babek particle, which functions to participate in immune response. Langerhans cells are antigen presenting cells that capture and process antigens that invade the skin and transmit them to T cells.
In a preferred embodiment, the compounds inhibit epidermal Langerhans cell maturation, antigen phagocytosis, and IL-23p19 secretion by down-regulating the neutral lipid level of epidermal Langerhans cells to treat psoriatic dermatitis.
In a preferred embodiment, the psoriatic dermatitis is Imiquimod (IMQ) -induced psoriatic dermatitis.
Wherein, imiquimod is a specific activator of Toll-like receptor (TLR) 7/8, and can be specifically combined with plasmacytoid dendritic cells (pDC) endosome TLR7 to induce pDC to secrete a large amount of interferon (interferon) -alpha. IMQ can induce and exacerbate disease when applied to psoriasis prone patients.
The experimental method comprises the following steps:
after 8-10 weeks old wild type C57BL/6 mice had depilated on their backs, 62.5mg of Imiquimod (IMQ) cream (5%, # H20030128, Sichuan medicine) was topically applied for 5 consecutive days to induce psoriatic lesions; the healthy control group was applied with an equal dose of vaseline (vaseline, VAS, #180102, shandongde). Mice were injected subcutaneously in the back with TOFA (# T6575, Sigma) or Phosphate Buffered Saline (PBS) in a volume of 100 μ l at a dose of 5mg/kg body weight starting the day before drug application, for 6 consecutive days. The experimental procedure is shown in figure 2.
The severity of skin lesions in mice was evaluated using the Psoriasis Area and Severity Index (PASI), which consists of an erythema index (0-4), a infiltrative index (0-4), and a scaling index (0-4). Skin thickness was measured with a vernier caliper. Paraffin-embedded skin tissue specimens were prepared and stained with hematoxylin-eosin.
The dorsal skin of the mice was harvested, epidermal single cell suspensions were prepared after true epidermal separation, resuspended in complete medium and cultured in vitro at 37 ℃ with or without addition of TOFA (10. mu.g/ml, # T6575, Sigma).
To determine the ability of LCs to phagocytose foreign antigens, freshly isolated epidermal cells were co-incubated with dextran-fluorescein isothiocyanate (dextran-FITC, 0.025%, # FD4, Sigma) for 45 min at 37 ℃ or 4 ℃, after which the cells were washed with PBS.
Flow cytometry analysis: after pretreatment with anti-CD 16/CD32 antibody (2.4G2, #553141, BD Biosciences), staining for 10 minutes with a fixed-activity stain (#564406, BDBiosciences) to differentiate dead and live cells, surface labeling was performed with anti-mouse I-a/I-E antibody (M5/114, #562363, BDBiosciences), anti-mouse CD45.2 antibody (104, #109832, Biolegend), and anti-mouse CD80 antibody (16-10a1, #104708, Biolegend). Intracellular staining cells were fixed and permeabilized with BD-Cytofix/Cytoperm (#51-2090KZ, BD-Biosciences), and incubated with anti-mouse IL-23p19 antibody (N71-1183, #565317, BDbiosciences) for 30 minutes at 4 ℃. Finally, the cells were detected using a BD-LSRFortessa cytometer and analyzed using FlowJo software.
The experimental results are shown below:
1. the PASI score showed that subcutaneous TOFA reduced IMQ-induced psoriatic skin inflammation (a down-regulation of the PASI score), down-regulated skin thickness, and improved histopathological characteristics (fig. 3-5). IMQ induced an increase in neutral lipid content in mouse epidermal LC compared to healthy controls; IMQ induced a decrease in lipid in epidermal LCs in mice following TOFA (FIG. 6, Bodipy)TM493/503 staining). This result suggests that lipid levels in epidermal LC may play an important role in modulating IMQ-induced psoriatic dermatitis.
2. To explore the effect of lipid content on LC immune function, we used TOFA to reduce fatty acid synthesis in epidermal LCs (FIG. 7, preparation of wild-type C57BL/6 mouse epidermal single cell suspension with or without addition of TOFA (10. mu.g/ml) at 37 ℃ for 18 hours, and final 4 hours with addition of BDGolgiStopTMProtein transport inhibitors. Use ofanti-MHC-II, CD45.2, CD80 antibodies and BodipyTM493/503 were stained and flow analyzed). TOFA significantly reduced neutral lipid levels in LCs cultured in vitro, with significant reductions in expression of cell surface maturation markers MHC-II and CD80, phagocytosis of dextran-FITC, and IL-23 secretion (FIGS. 8-11, preparation of wild-type C57BL/6 mouse epidermal single cell suspension with or without TOFA (10. mu.g/ml) at 37 ℃ for 18 hours, and final 4 hours of BDGolgiStop additionTMProtein transport inhibitors. Using anti-MHC-II, CD45.2, CD80 antibodies and BodipyTM493/503 and flow analysis), indicating that the neutral lipid content of epidermal LCs is highly correlated with the immune function, further suggesting that lipid metabolism disorders may affect the development of psoriasis by affecting the immune function of epidermal LCs.
The foregoing is merely an example of the present invention and common general knowledge of known techniques and features in the schemes is not described herein in detail. It should be noted that, for those skilled in the art, without departing from the present invention, several changes and modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicability of the patent. The scope of the claims of the present application shall be defined by the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.
The embodiments of the present invention have been described in detail, and the principle and the implementation of the present invention are explained in the present document by applying specific embodiments, and the above description of the embodiments is only used to help understanding the method of the present invention and the core idea thereof. Meanwhile, those skilled in the art should also be able to make modifications or variations to the present invention based on the detailed description of the invention and the scope of the application, which falls within the scope of the protection of the present invention. In view of the above, the present disclosure should not be construed as limiting the invention.
Claims (10)
1. The application of a compound shown in the following formula I or a pharmaceutically acceptable salt, a deuteron, a solvate, a metabolite or a prodrug thereof in preparing a medicament for treating psoriasis-like dermatitis,
wherein R is1And R2Identical or different and is hydrogen, halogen, hydroxy, C1-12Alkyl or C1-12An alkoxy group.
2. Use of a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt, deutero-compound, solvate, metabolite or prodrug thereof in the manufacture of a medicament for the treatment of psoriatic dermatitis,
wherein R is1And R2Identical or different and is hydrogen, halogen, hydroxy, C1-12Alkyl or C1-12An alkoxy group.
3. Use of a pharmaceutical formulation comprising a compound of formula I or a pharmaceutically acceptable salt, deutero-compound, solvate, metabolite or prodrug thereof in the manufacture of a medicament for the treatment of psoriatic dermatitis,
wherein R is1And R2Identical or different and is hydrogen, halogen, hydroxy, C1-12Alkyl or C1-12An alkoxy group.
4. The use according to claim 3, wherein the pharmaceutical formulation further comprises a pharmaceutically acceptable pharmaceutical excipient.
5. The use of claim 3, wherein the pharmaceutical formulation is a solid tablet, an oral liquid, a capsule, a drop pill, an ointment, a gel formulation, a transdermal patch, a microemulsion formulation, or an aerosol;
preferably, the pharmaceutical formulation is an ointment, a gel formulation, a transdermal patch, a microemulsion formulation or an aerosol.
6. The use according to claim 3, wherein the pharmaceutical excipient comprises one or more of a matrix material, a humectant, a pH adjuster, a surfactant, a preservative, a chelating agent, and a stabilizer.
7. The use according to claim 2 or 3, wherein the pharmaceutical composition or the pharmaceutical formulation further comprises one or more of methotrexate, tretinoin, cyclosporin A, etanercept, infliximab, adalimumab, and ursinumab.
8. Use according to any one of claims 1 to 6, characterized in that R1And R2Identical or different and is hydrogen, hydroxy, C1-6Alkyl or C1-6An alkoxy group;
preferably, R1And R2Identical or different and hydrogen, hydroxy, methyl or methoxy;
more preferably, the compound is 5-tetradecyloxy-2-furancarboxylic acid.
9. Use according to any one of claims 1 to 6, characterized in that said compound is for the treatment of psoriatic dermatitis by inhibiting the inhibition of epidermal Langerhans cell immune function; preferably, the compounds treat psoriatic dermatitis by down-regulating neutral lipid levels of epidermal langerhans cells, inhibiting epidermal langerhans cell maturation, antigen phagocytosis and IL-23p19 secretion.
10. Use according to any one of claims 1 to 6, characterized in that said psoriatic dermatitis is imiquimod-induced psoriatic dermatitis.
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