JP2001220355A - Mast cell activation inhibitor comprising PPARβ / δ and γ ligands - Google Patents

Abstract

(57) [Problem] An object of the present invention is to provide a novel mast cell activation inhibitor. It is a further object of the present invention to provide a therapeutic agent which has an excellent therapeutic effect on diseases involving mast cells, such as allergic diseases, and has reduced side effects. SOLUTION: Peroxisome proliferator-activated receptor β
A mast cell activation inhibitor comprising a compound that activates / δ and γ as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a compound (hereinafter, referred to as "ligand") that activates peroxisome proliferator-activated receptor (hereinafter sometimes referred to as "PPAR") β / δ and γ of mast cells. More specifically, the present invention relates to adaptation of a compound that suppresses mast cell activation through activation of PPARβ / δ and γ to a disease involving mast cells such as an allergic disease.

[0002]

BACKGROUND OF THE INVENTION Mast cells play a major role in allergic inflammation. That is, when a living body is sensitized to a certain antigen, immunoglobulin E (IgE) or immunoglobulin G (IgG) specific to the antigen is obtained.
Is produced. Of these, mast cell sensitization is established by binding of IgE to a receptor on the mast cell. These mast cells trigger allergic inflammation by releasing various chemical messengers in response to externally entered antigens. Furthermore, it has also been revealed that mast cells enhance the delayed allergic reaction by producing several types of cytokines.

[0003] Among diseases involving mast cells, allergic diseases represented by bronchial asthma, allergic conjunctivitis, allergic rhinitis, atopic dermatitis and the like are known. In addition, mast cells produce growth factors for fibroblasts as well as inflammatory cytokines upon activation, and thus have been pointed out as important in tissue fibrosis.

At present, steroids are the most effective therapeutic agents for allergic diseases, and are widely used in clinical practice. The mechanism of action of steroids is now well known. That is, the steroid, after entering the cell, binds to and activates a unique receptor present in the cytoplasm. The activated steroid-receptor complex translocates into the nucleus to stimulate transcriptional activation of a particular target gene. Alternatively, the transcriptional activity is suppressed by interacting directly or indirectly with other transcription factors.

[0005] Nuc in cells in the inflammatory response of living organisms
near factor-κB (NF-κB) or act
It is important to induce inflammatory proteins such as cytokines, cell adhesion molecules, and proteases following activation of transcription factors such as ivator protein-1 (AP-1). These transcription factors also play important roles in the activation of mast cells, which play a central role in allergic inflammation. Mol. Cell. Bio
l. (1995) 15, 943-953. Robe
rt, et al. And the like, the main mechanism of the anti-inflammatory effect of steroid drugs is such NF-κB
It has been reported that the activation of transcription factors such as AP1 and AP-1 is suppressed.

[0006] On the other hand, steroids have a problem of side effects peculiar to them, and it is known that resistance to the steroids occurs and inflammation recurs after discontinuation of use. These causes include a decrease in the expression of steroid receptors due to the use of steroids.

[0007] It is also known that systemic side effects occur when absorbed into the body when taken internally or used externally. Therefore, the use of steroids is subject to caution and certain restrictions.

[0008]

That is, an object of the present invention is to provide a novel mast cell activation inhibitor. It is a further object of the present invention to provide a therapeutic agent which has an excellent therapeutic effect on diseases involving mast cells, such as allergic diseases, and has reduced side effects. We consider PP
The present inventors have discovered that ARβ / δ and γ are expressed along with mast cell activation, and that these activators suppress mast cell activation, leading to the present invention.

[0009]

That is, the present invention is a mast cell activation inhibitor comprising as an active ingredient a compound that activates peroxisome proliferator-activated receptors β / δ and γ.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail. The present invention relates to a mast cell activation inhibitor containing a compound that activates peroxisome proliferator-activated receptors β / δ and γ as an active ingredient. Furthermore, the present invention relates to a therapeutic agent for a disease involving mast cells, comprising the mast cell activation inhibitor.

The peroxisome proliferator-activated receptor (PPAR) of the present invention includes various steroids, vitamin D3,
It is a member of the nuclear receptor superfamily similar to thyroid (thyroid hormone) and retinoic acid.

The PPARβ / δ and γ ligands of the present invention include, for example, Proc. Natl. Acad. Sc
i. USA. (1997) 94, 4312-4217.
B. M. Forman, et al. Or C
ell (1995) 83, 803-812.
M. Forman, et al. As disclosed in such a carba prostacyclin as PPAR [beta] / [delta] ligand, and as the PPARγ ligand prostaglandin _{D 2 (PGD 2), D} 12 - prostaglandin J ₂ (Δ ¹² -PGJ ₂₎ , 15deoxy-prostaglandin J ₂ (15d-PGJ ₂ ), troglitazone and the like.

The mast cell-related diseases of the present invention include, for example, various allergic diseases such as bronchial asthma, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, or organ fibrosis.

When used for treatment, the mast cell activation inhibitor of the present invention is administered by oral, suppository, transdermal, inhalation, nasal, subcutaneous, intramuscular, intravenous, intraarterial, or other administration methods.

For oral administration, a solid preparation or
It can be a liquid formulation. Formulations include, for example, tablets, pills, powders, granules, solutions, suspensions and capsules. When preparing tablets, excipients such as lactose, starch, calcium carbonate, crystalline cellulose, or silicic acid according to a conventional method; binders such as carboxymethyl cellulose, methyl cellulose, calcium phosphate, or polyvinylpyrrolidone; sodium alginate; Disintegrators such as sodium bicarbonate, sodium lauryl sulfate and monoglyceride stearate; lubricants such as glycerin; absorbents such as kaolin and colloidal silica; talc;
It is formulated using additives such as lubricants such as granular boric acid.

[0016] Pills, powders or granules are also formulated in the usual manner using additives as described above.

Liquid preparations such as liquid preparations and suspensions are also formulated in accordance with ordinary methods. As the carrier, for example, glycerol esters such as tricaprylin, triacetin, and fatty acid ester of iodized poppy oil; water; alcohols such as ethanol; and oily bases such as liquid paraffin, coconut oil, soybean oil, sesame oil, and corn oil are used. .

The above-mentioned powders, granules, liquid preparations and the like can be wrapped in capsules such as gelatin.

The pharmaceutically acceptable carrier in the present specification includes other adjuvants, fragrances, stabilizers, and preservatives usually used as necessary.

Examples of the dosage form of the drug for transdermal administration include ointments, creams, lotions, liquids and the like.

The base of the ointment includes, for example, fatty oils such as castor oil, olive oil, sesame oil and safflower oil; lanolin; white, yellow or hydrophilic petrolatum; wax; oleyl alcohol, isostearyl alcohol, octyldodecanol, hexyldecanol and the like. Higher alcohols; glycerin, diglycerin, ethylene glycol,
Glycols such as propylene glycol, sorbitol and 1,3-butanediol are exemplified. In addition, ethanol, dimethyl sulfoxide, polyethylene glycol, or the like may be used as a solubilizing agent. If necessary, a preservative such as paraoxybenzoic acid ester, sodium benzoate, salicylic acid, sorbic acid, boric acid and the like; an antioxidant such as butylhydroxyanisole and dibutylhydroxytoluene may be used.

In order to promote percutaneous absorption, an absorption enhancer such as diisopropyl adipate, diethyl sebacate, ethyl caproate, ethyl laurate and the like may be added. In order to stabilize, the compound of the present invention has α, β
Alternatively, it can be used after forming an inclusion compound with γ-cyclodextrin or methylated cyclodextrin.

The ointment can be manufactured by a usual method. As a cream, an oil-in-water type cream is preferable in order to stabilize the compound of the present invention. As the base, fatty oils, higher alcohols, glycols and the like are used as described above, and emulsifiers such as diethylene glycol, propylene glycol, sorbitan monofatty acid ester, polysorbate 80 and sodium lauryl sulfate are used. Further, a preservative, an antioxidant and the like as described above may be added as necessary. Further, as in the case of the ointment, it can also be used as an inclusion compound of cyclodextrin and methylated sictodextrin. Creams can be manufactured by usual methods.

Examples of the lotion include suspension type, emulsion type,
Solution-type lotions are included. The suspension lotion is obtained by using a suspending agent such as sodium alginate, tragacanth, sodium carboxymethylcellulose, and adding an antioxidant, a preservative, and the like as necessary.

The emulsifying lotion can be obtained by an ordinary method using an emulsifying agent such as sorbitan monofatty acid ester, polysorbate 80, sodium lauryl sulfate and the like.

The solution type lotion is preferably an alcohol type lotion, and can be obtained by an ordinary method using an alcohol such as ethanol. Examples of the liquid preparation include those dissolved in an alcohol solution such as ethanol, to which an antioxidant, a preservative, and the like are added as necessary.

In addition to these dosage forms, dosage forms such as pasta, poultice, aerosol and the like can be mentioned. Such a preparation can be produced by a usual method.

Formulations for nasal administration are provided as liquid or powdered compositions. As a base of the liquid agent, water, saline, phosphate buffer, acetate buffer, etc. are used,
Further, it may contain a surfactant, an antioxidant, a stabilizer, a preservative, and a viscosity-imparting agent. As a base of the powdery agent,
Water-absorbing ones are preferable, for example, water-soluble polyacrylates such as sodium polyacrylate, calcium polyacrylate and ammonium polyacrylate, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and cellulose such as sodium carboxymethylcellulose. Lower alkyl ethers,
Polyethylene glycol, polyvinylpyrrolidone, amylose, pullulan and the like, and celluloses such as crystalline cellulose, α-cellulose and crosslinked sodium carboxymethylcellulose, which are poorly water-soluble, hydroxypropyne starch, carboxymethyl starch, crosslinked starch, amylose, amylopectin, pectin, etc. Starches, gelatin, casein, proteins such as casein sodium, gum arabic, tragacanth gum, gums such as glucomannan,
Examples include polyvinyl polypyrrolidone, cross-linked polyacrylic acid and salts thereof, cross-linked polyvinyl alcohol, cross-linked vinyl polymers such as polyhydroxyethyl methacrylate, and the like, and these may be used as a mixture. Further, an antioxidant, a coloring agent, a preservative, a preservative, a preservative, and the like may be added to the powder. Such a liquid or powdery agent can be administered using, for example, a spray device or the like.

Formulations for administration by injection are provided as sterile aqueous or water-insoluble solutions, suspensions, or emulsifiers. Non-aqueous solutions or suspensions include, for example, pharmaceutically acceptable carriers such as vegetable oils such as propylene glycol, polyethylene glycol or olive oil, injectable organic esters such as ethyl oleate, iodinated poppy oil fatty acid esters. And Such formulations may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, and stabilizing agents and may provide for sustained release. These solutions, suspensions and emulsifiers can be sterilized by appropriate treatment such as filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. In addition, a sterile solid preparation can be manufactured and dissolved in sterile water or a sterile solvent for injection immediately before use.

Further, the compound of the present invention may contain α, β, or γ-
It is also possible to form an inclusion compound with cyclodextrin or methylated cyclodextrin before use. Also, an injection in the form of a liposome may be used.

[0031]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but it goes without saying that the scope of the present invention is not limited to these Examples.

[Example 1] PP in mouse mast cells and human mast cells
Bone marrow cells collected from 2-month-old BALB / c mice expressing AR were transformed with recombinant mouse interleukin-3 (IL-3, IL-3).
10% FCS (GIB) in the presence of PeproTech
RPMI1640 containing CO Life Tech)
Mast cells (mBMMC) were obtained by culturing in a culture solution (GIBCO Life Tech) for 5 weeks.
5 μg / mL of a trinitrophenyl group-specific immunoglobulin E (anti-TNP IgE, P
(Harmingen) at 37 ° C. for 12 hours.
1 × 10 ⁶ cells were treated with dinitrophenylated bovine serum albumin (DNP-BSA, Far East Pharmaceutical Co., Ltd.)
Stimulation was performed at a concentration of 0 ng / mL for 6 hours. Or 0.1
The cells were stimulated with μg / mL A23187 (Sigma) for 6 hours.

A mononuclear cell fraction was prepared from heparin-treated human umbilical cord blood using Ficoll Pack (Pharmacia), and 80 ng / mL SCF (PeproTec) was used.
h) and 50 ng / mL IL-6 (PeproTe
In the presence of 5% carbon dioxide, the cells were cultured at 37 ° C. for 10 weeks to obtain human mast cells (HCMC) with a purity of 99% or more. HCMC for human myeloma I
After reacting with gE (Cappel) at 37 ° C. for 12 hours, the plate was washed with a culture solution. 1 × 10 ⁶ HC with 1 μg / mL anti-human IgE-rabbit serum (Chemicon)
MCs were stimulated. Alternatively, 0.1 μg / mL calcium ionophore A23187 (stimulant) (Sigma)
Co., Ltd.) and 5 ng / mL phorbol ester (TPA, S
(Sigma) for 6 hours.

Changes in the expression level of PPAR in mast cells were determined by RT
-Checked by PCR method. That is, from mast cells to total R
After extracting NA with an RNA extraction kit (QIAGEN), cDNA was synthesized by a reverse transcription reaction (Pharm
acia). Furthermore, PCR reaction was performed using primers specific to PPAR (Takara Shuzo). Primers used were mPPARα: 5'-CCTGCAGAGCAACAATCCAG-3 '(upstream), CCC
GTTATTTAATGGCGAA-3 '(downstream), mPPARβ / δ: 5'-GTCATGGATCCGCCACAGGAGGAGACCCCT-3' (u
pstream), 5'-GGGAGGAATTCTGGGAGAGGTCTGCACAGC-3 '(dow
nstream), mPPARγ: 5'-GAGATGCCATTCTGGCCCACCAACTTCGGA-3 '(upst
ream), 5'-TATCATAAATAAGCTTCAATCGGATGGTTC-3 '(downst
ream), hPPARα: 5'-CCAGTATTTAGGACGCTGTCC-3 '(upstream), 5'
-AAGTTCTTCAAGTAGGCCAGC-3 '(downstream), hPPARβ / δ: 5'-AACTGCAGATGGGCTGTGAC-3' (upstream),
5'-GTCTCGATGTCGTGGATCAC-3 '(downstream), hPPARγ: 5'-TCTCTCCGTAATGGAAGACC-3' (upstream), 5'-
GCATTATGAGACATCCCCAC-3 '(downstream), hPPARγ2: 5'-GCGATTCCTTCACTGATAC-3' (upstream), 5'-
GCATTATGAGACATCCCCAC-3 '(downstream), glyceraldehyde-3-phosphate dehydrogenase (G3PDH):
5'-ACCACAGTCCATGCCATCAC-3 '(upstream), 5'-TCCACCACC
CTGTTGCTGTA-3 '(downstream).

As conditions, 35 cycles of 1) denaturation (95 ° C. for 30 seconds), 2) annealing (55 ° C. for 1 minute), and 3) extension reaction (72 ° C. for 1 minute) were performed. P
A part of the CR product was electrophoresed using 2% agarose gel (Nippon Gene) containing 0.5 μg / mL ethidium bromide (Sigma), visualized by ultraviolet irradiation, and photographed.

As shown in FIGS. 1 and 2, mBMMC
(A) expresses PPARβ / δ and γ, and HCMC (B) expresses PPARβ / δ, γ1, and γ2.
In mBMMC, antigens such as DNP-BSA and A2318
7 induced PPARγ expression. In HCMC, expression of PPARγ2 was induced by a combination treatment of anti-IgE antibody or A23187 with TPA. Since the amounts of G3PDH, which is a housekeeping gene, are equal, it is shown that the amounts of mRNA contained in the samples are almost equal.

Example 2 Inhibition of TNFα Production of Cultured Mast Cells of Mice Bone marrow cells collected from 2-month-old BALB / c mice were subjected to recombinant mouse interleukin-3 (IL-3).
10% FCS (GIBCO LifeTech) in the presence
Culture medium (GIBCO Li) containing
mast cells (mBMMC) were obtained by culturing the cells for 5 weeks in FeTech. 5 μg / mL in culture
Immunoglobulin E specific for trinitrophenyl group
(Anti-TNP IgE, Pharmingen
Sensitized at 37 degrees for 12 hours. During the sensitization time, a drug was added, or the drug treatment was performed by adding only ethanol as a lysis solution to a final concentration of 0.5%. 1x
10 ⁵ cells were supplemented with 10 n of dinitrophenylated bovine serum albumin (DNP-BSA, Far East Pharmaceutical) as an antigen.
Stimulation was performed at a concentration of g / mL for 6 hours. TNFα in supernatant
The content was measured by an ELISA method (Genzyme). Granulocyte / macrophage colony stimulating factor (GM-CSF) was also measured using the same sample (Ge
nzyme).

As apparent from FIGS. 3A and 3B, PPARγ
The ligand 15deoxy-PGJ ₂ , troglitazone, and the PPARβ / δ ligand carbaprostacyclin inhibited TNFα production by mBMMM in a concentration-dependent manner. Bezafibrate, ETYA, which is a PPARα ligand, had no inhibitory effect. 15deoxy-PGJ ₂ and troglitazone are GM-
CSF production was also suppressed in a concentration-dependent manner.

[Example 3] Inhibition of histamine release from mouse mast cells cultured in the same manner as in Example 1
After sensitization with P IgE, 1 × 10 ⁵ cells were stimulated with antigen, DNP-BSA, at a concentration of 10 ng / mL. During the sensitization time, a drug was added, or the drug treatment was performed by adding only ethanol as a lysis solution to a final concentration of 0.5%. The concentration of the added drug was 10 μM 15
deoxy-PGJ ₂ , 50 μM troglitazone, 10
μM carbaprostacyclin, 100 μM bezafibrate. The concentration of the drug was set at a stimulation time of 30 minutes, and the histamine content in the cells after the reaction and in the supernatant was measured using a histamine autoanalyzer (Branluve).
And the histamine release rate was calculated.

As is apparent from FIG. 4, the 15 deoxy-PGJ ₂ which is a PPARγ ligand, troglitazone and the carbaprostacyclin which is a PPARβ / δ ligand inhibited the histamine release reaction from mBMMC.

Example 4 Inhibition of cytokine production in cultured human mast cells Ficoll pack (P
moncia), and a mononuclear cell fraction was prepared.
0 ng / mL SCF (PeproTech) and 50
In the presence of ng / mL IL-6 (PeproTech), the cells were cultured for 10 weeks at 37 ° C. under a carbon dioxide concentration of 5% to obtain human mast cells (HCMC) with a purity of 99% or more.

HCMC was converted to human myeloma-derived IgE (C
(Appel) at 37 ° C. for 12 hours, and then washed with a culture solution. The drug dissolved in ethanol during the sensitization time was added to the culture solution so that the final concentration of ethanol was 0.5%, and the drug was treated. 1 μg / mL anti-human Ig
1 × 10 ⁵ HCMC were stimulated with E-rabbit serum (Chemicon), and after 6 hours, mast cells were centrifuged and the GM-CSF content in the cell supernatant obtained was measured by ELISA (Genzyme).

As apparent from FIG. 5, the PPARγ ligands PGD ₂ , D ¹² -PGJ ₂ , and 15deoxy-P
GJ ₂ , troglitazone and the PPARβ / δ ligand carbaprostacyclin are GM-mediated by HCMC.
CSF production was inhibited in a concentration-dependent manner. On the other hand, PPARα
The ligand ETYA (5, 8, 11, 14-Eic
osatraynoic acid) did not show any inhibitory action.

Example 5 Inhibition of Histamine Release from Cultured Human Mast Cells In the same manner as in Example 3, human mast cells were stimulated. The concentration of the added drug was 10 µM PGD ₂ , 10 µMD ¹² -P
GJ ₂ , 10 μM 15 deoxy-PGJ ₂ , 50 μM troglitazone, 10 μM carbaprostacyclin. The stimulation time was 30 minutes, and the histamine content in the cells after completion of the reaction and in the supernatant was measured with a histamine autoanalyzer (manufactured by Blanc-Roube) to calculate the histamine release rate.

As is apparent from FIG. 6, the PPARγ ligands PGD ₂ , D ¹² -PGJ ₂ , and 15deoxyPG
J ₂ and the PPARβ / δ ligand carbaprostacyclin inhibited the histamine release reaction from HCMC.

[Example 6] P on the expression of PPAR in mouse mast cells cultured
Influence of PAR ligand Mice cultured mouse mast cells were cultured in a culture solution containing 4 ng / mL of IL-3 at 5 μg / mL of anti-TNP IgE.
(Pharmingen) at 37 ° C. for 12 hours. During the sensitization time, a drug was added, or the drug treatment was performed by adding only ethanol as a lysis solution to a final concentration of 0.5%. 1 × 10 ⁶ cells were converted to antigen D
NP-BSA (Kyokuto Pharmaceutical) was stimulated at a concentration of 10 ng / mL for 6 hours. After extracting total RNA from mast cells with an RNA extraction kit (QIAGEN), cDNA was synthesized by reverse transcription reaction using kit (Pharmac).
ia). Furthermore, PCR was performed using a primer specific to PPAR.
Reaction was performed (Takara Shuzo). The primer used was mPPARγ: 5′-GAGATGCCATTCTGGCCCACCAACTTCGGA-3 ′ (upst
ream), 5'-TATCATAAATAAGCTTCAATCGGATGGTTC-3 '(downst
ream), glyceraldehyde-3-phosphate dehydrogenase (G3PDH):
5'-ACCACAGTCCATGCCATCAC-3 '(upstream), 5'-TCCACCACC
CTGTTGCTGTA-3 '(downstream). As reaction conditions, 1) denaturation (95 ° C. for 30 seconds), 2) annealing (55 ° C. for 1 minute), 3) extension reaction (72 ° C. for 1 minute)
Was repeated 35 times. 0.5 part of PCR product
Electrophoresis was performed using a 2% agarose gel (Nippon Gene Co., Ltd.) containing μg / mL ethidium bromide (Sigma), visualized by ultraviolet irradiation, and photographed.

As shown in FIG. 7, the mRN of PPARγ
A expression levels did not decrease after PPARγ ligand treatment. G3PDH, a housekeeping gene
Are equivalent, the mR contained in the sample
It is shown that the NA amounts are almost the same.

[0048]

EFFECT OF THE INVENTION It has been shown that prostaglandin derivatives and known thiazolidine compounds serving as ligands of PPARγ and β / δ in mast cells suppress cytokine production and histamine release reaction associated with mast cell activation. Was. Therefore, it is expected that ligands for PPARγ and β / δ will be effective therapeutic agents for allergic diseases involving mast cells. This indicates that similar results were obtained not only in mice but also in human mast cells, suggesting an effect in humans. Furthermore, since PPAR ligands do not have the effect of lowering the expression level of PPAR, they are expected to be safe drugs for allergic diseases that can be used to avoid relapse of allergic inflammation after discontinuation of use such as steroids. Is done.

[Brief description of the drawings]

FIG. 1 shows the results of RT-PCR of PPAR expression in mBMMC.

FIG. 2 shows PPAR expression in HCMC
It was examined by T-PCR.

[Fig. 3] Fig. 3 is a graph showing PPs on TNFα production or GM-CSF production by antigen stimulation of cultured mouse mast cells.
This shows the effects of ARγ and β ligands,
It was also shown that the AR ligand was dose-dependent. The horizontal axis shows the concentration of the added PPAR ligand, and the vertical axis shows the production of TNFα by antigen stimulation when no drug was added, as a percentage.

FIG. 4 shows the effects of PPARγ and β ligands on the histamine release reaction of mouse cultured mast cells upon antigen stimulation. The concentration of the added drug is ()
The values are shown as μM concentrations. The vertical axis indicates the histamine release rate.

FIG. 5 shows the effects of PPARγ and β ligand on GM-CSF production of anti-IgE antibody stimulation of cultured human mast cells, and shows the dose dependence of PPAR ligand. The horizontal axis is the added PPAR
The ordinate indicates the concentration of the ligand, and the ordinate indicates the anti-IgE when no drug was added.
It is a GM-CSF production by antibody stimulation expressed as a percentage.

FIG. 6 shows the effects of PPARγ and β ligand on histamine release reaction of anti-IgE antibody stimulation of cultured human mast cells. The vertical axis shows the rate of inhibition of the histamine release reaction when no drug is added.

FIG. 7 shows the effect of PPAR ligand on PPAR expression.

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Claims (3)

[Claims] 1. Peroxisome proliferator-activated receptor β
/ A mast cell activation inhibitor comprising a compound that activates δ and γ as an active ingredient. 2. A therapeutic agent for a disease involving mast cells, comprising the mast cell activation inhibitor according to claim 1. 3. The therapeutic agent according to claim 2, wherein the disease involving mast cells is an allergic disease or organ fibrosis.