WO2007061094A1 - Pparアゴニスト含有医薬 - Google Patents
Pparアゴニスト含有医薬 Download PDFInfo
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- WO2007061094A1 WO2007061094A1 PCT/JP2006/323601 JP2006323601W WO2007061094A1 WO 2007061094 A1 WO2007061094 A1 WO 2007061094A1 JP 2006323601 W JP2006323601 W JP 2006323601W WO 2007061094 A1 WO2007061094 A1 WO 2007061094A1
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- ppar
- agonist
- corneal epithelial
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- meibomian gland
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/04—Artificial tears; Irrigation solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/26—Radicals substituted by sulfur atoms
Definitions
- the present invention relates to a growth promoter for meibomian gland epithelial cells or corneal epithelial cells, containing PPAR (Peroxisome Proliferator Activated Receptor) ⁇ or ⁇ agonist as an active ingredient. .
- PPAR Peroxisome Proliferator Activated Receptor
- the meibomian glands are lipid-producing glands contained in the upper and lower eyelids (eyelids), and the opening force located on the conjunctival side from the eyelashes (lashes) of the eyelids also secretes lipids.
- the oil layer that makes up tears is composed of lipids supplied from the meibomian glands, and prevents evaporation of tears caused by ocular surface forces.
- the function of the meibomian gland decreases and the amount of lipid secretion decreases, so dry evaporation with dry tears, keratoconjunctival epithelial disorder associated with dry eye, It is known to cause corneal ulcers.
- the cornea consists of an ectoderm epithelium and a mesodermal outer boundary plate (Bowman membrane) 'parenchyma' inner boundary plate (Desme membrane) endothelium. Since the cornea is located in the forefront of the eyeball, it is affected by the environment of the outside world, and as a result, various obstacles occur. Diseases associated with corneal epithelial cell damage or loss include dry eye syndrome, corneal ulcer, punctate superficial keratopathy, corneal epithelial fistula, ocular allergic diseases with corneal lesions such as spring catarrh and atopic keratoconjunctivitis It is done.
- PPAR is a kind of nuclear receptor expressed in most vertebrates, and is considered to be a group of transcription factors closely related to intracellular sugar and lipid metabolism and cell differentiation. ing. As subtypes, ⁇ , ⁇ , and ⁇ types are known. PPAR ⁇ is sometimes expressed as PPAR ⁇ (Non-patent Document 1).
- Non-patent Document 2 As for the distribution of PPAR in the eye tissue, it is known that PPAR a and ⁇ are expressed and expressed in corneal epithelial cells of rabbits (Non-patent Document 2).
- PPAR activation activity 5 [4— (6-Methoxy-1- 1-methyl 1H— Benzimidazole-2-ylmethoxy) benzyl] thiazolidine 1, 2, 4 dione can be used as a therapeutic agent for keratoconjunctival disorders (Patent Documents 1 and 2), and for the treatment of eye diseases (conjunctivitis, dry eye syndrome, keratitis, etc.) It has been reported that PPARa, ⁇ or ⁇ agost is administered (Patent Document 3).
- PPAR a is known to be distributed in the liver, kidney, etc., and to act on lipid metabolism 'transport, and it has also been reported that its antigen can be used as a therapeutic agent for corneal diseases. Speak (Patent Document 4).
- PPAR ⁇ agonists there have been reports on the promotion of proliferation and differentiation of rat sebaceous gland epithelial cells (Non-patent Document 3) and the promotion of skin wound healing (Non-patent Document 4). There is.
- Patent Document 5 Other methods include stimulating ⁇ -cell proliferation by administering non-thiazolidinedione PPAR ligands and GLP-1 derivatives (Patent Document 5), and PPAR ⁇ -agonist pioglitazone is leukemia cells and prostate cancer cells. It has been known to inhibit the growth of the plant (Patent Document 6).
- Patent Document 1 International Publication No. 2005Z039574 Pamphlet
- Patent Document 2 JP 2001-39976 A
- Patent Document 3 International Publication No. 2002Z076177 Pamphlet
- Patent Document 4 Japanese Patent Laid-Open No. 2005-008570
- Patent Document 5 International Publication No. 2002Z69994 Pamphlet
- Patent Document 6 International Publication No.1998Z25598 pamphlet
- Non-Patent Document 1 J Med Chem 2000, 43: 527-550
- Non-Patent Document 2 J Biol Chem 2000, 275: 2837
- Non-Patent Document 3 Molecular Genetic and Metabolism 2001, 74: 362-369
- Non-Patent Document 4 Am J Clin Dermatol 2003, 4 (8): 523-530
- the subject of the present invention is a meibomian gland that can be a fundamental treatment for eye diseases such as dry eye.
- eye diseases such as dry eye.
- a drug capable of promoting the proliferation of epithelial cells and corneal epithelial cells and to provide a therapeutic agent for eye diseases such as meibomian gland dysfunction 'dry tear evaporation type dry eye' using the promoter is there.
- the present invention includes at least the following contents.
- a meibomian gland epithelial cell growth promoter containing PPARa or ⁇ agonist as an active ingredient containing PPARa or ⁇ agonist as an active ingredient.
- a corneal epithelial cell growth promoter containing PPAR «or ⁇ agonist as an active ingredient (1) A corneal epithelial cell growth promoter containing PPAR «or ⁇ agonist as an active ingredient.
- a meibomian gland dysfunction therapeutic agent containing PPAR «or ⁇ agonist as an active ingredient containing PPAR «or ⁇ agonist as an active ingredient.
- a corneal epithelial cell growth promoter containing PPAR ⁇ agonist as an active ingredient is provided.
- a therapeutic agent for corneal epithelial disorder containing PPAR ⁇ agonist as an active ingredient.
- PPAR a or ⁇ agonist is the general formula (I)
- A represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
- B is —CO—, —NH—, — (CH) — S—
- group force represents a selected linker
- X and Y are the same or different and represent a carbon atom or a nitrogen atom
- Z represents an oxygen atom, a sulfur atom or —CH 3;
- Ar has 1 to 3 substituents and may represent an aromatic ring group that is a 5- to 6-membered ring,
- R and R are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- R represents hydrogen, a halogen atom or an alkyl group having 1 to 6 carbon atoms
- the agent according to any one of (1) to (5) which is a compound represented by the formula: or a pharmacologically acceptable salt thereof.
- PPAR ⁇ agonist is general formula (II)
- ⁇ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
- B is — (CH 2) —S and —O— (CH 2) ⁇ 0- (where n represents an integer of 1 to 3)
- the linker selected from the group of:
- X and Y are the same or different and represent a carbon atom or a nitrogen atom
- Z represents an oxygen atom, a sulfur atom or —CH 3;
- Ar has 1 to 3 substituents and may represent an aromatic ring group that is a 5- to 6-membered ring, R and R are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- R represents hydrogen, a halogen atom or an alkyl group having 1 to 6 carbon atoms
- the PPAR ⁇ -agost is (4- (3- (4 acetyl-3-hydroxy-2-propyl) phenoxy) propoxyphenoxy) acetic acid, (2-methyl-4 (((4-methyl-2- (4 (Trifluoromethyl) phenyl) 5- (thiazolyl) methyl) thio) phenoxy) acetic acid or (4 — (((2- (3-fluoro-4 (trifluoromethyl) phenol) —4—
- the agent according to (11) or (12) which is methyl-5-thiazolyl) methyl) thio) -2-methylphenoxy) acetic acid or a pharmacologically acceptable salt thereof.
- PPAR agarost force 2 (4— (4-chlorobenzoyl) phenoxy) 2-methylpropionic acid 1-methylethyl ester or (((4-chloromethyl 6- ((2, 3 dimethyl The agent according to (11), which is phenyl) amino) -2-pyrimidinyl) thio) acetic acid or a pharmacologically acceptable salt thereof.
- a method for promoting the growth of meibomian gland epithelial cells comprising administering an effective amount of PPAR ⁇ or ⁇ agonist to a subject in need of promoting the growth of meibomian gland epithelial cells.
- a method for promoting the proliferation of corneal epithelial cells comprising administering an effective amount of PPAR ⁇ or ⁇ agonist to a subject in need of promoting the proliferation of corneal epithelial cells.
- a method for treating dry tear evaporation type dry eye comprising administering an effective amount of PPAR ⁇ or ⁇ agonist to a patient suffering from dry tear evaporation type dry eye.
- a method for promoting the proliferation of meibomian gland epithelial cells comprising administering an effective amount of PPAR ⁇ agost to a subject in need of promoting the proliferation of meibomian gland epithelial cells.
- a method for promoting the proliferation of corneal epithelial cells comprising administering an effective amount of PPAR ⁇ agost to a subject in need of promoting the proliferation of corneal epithelial cells.
- a method for treating tear evaporation enhanced dry eye comprising administering an effective amount of PPAR ⁇ agonist to a patient suffering from tear evaporation enhanced dry eye.
- a novel meibomian gland epithelial cell proliferation promoter or corneal epithelial cell proliferation promoter is provided, and the promoter promotes the proliferation of meibomian gland epithelial cells and corneal epithelial cells.
- the therapeutic agent of the present invention can be effectively used for the treatment and improvement of diseases such as meibomian gland dysfunction, corneal epithelial disorder, and tear evaporation enhanced dry eye.
- FIG. 1 shows cultured human corneal epithelial cells (upper), cultured rabbit corneal epithelial cells (middle), and And PPAR ⁇ , ⁇ , and ⁇ mRNA expression in cultured salmeibom gland epithelial cells (bottom).
- the present invention provides a meibomian gland epithelial cell growth promoter containing PPARa or ⁇ agost as an active ingredient.
- the promoter promotes the growth of meibomian gland epithelial cells.
- the present invention also provides a corneal epithelial cell growth promoter comprising PPAR or ⁇ agost as an active ingredient.
- the promoter promotes proliferation of corneal epithelial cells.
- the cell growth promoter referred to in the present invention means both those having the action of promoting cell division and increasing the number of cells, and those having the action of suppressing cell death and increasing the number of cells.
- the promoter of the present invention contains PPARa or ⁇ agonist as an active ingredient.
- PPAR a ligand refers to a substance that has the action of binding to PPAR a and activating PPAR a.
- the PPAR ⁇ ligand is a substance having an action of binding to PPAR ⁇ and activating PPAR ⁇ .
- Examples of the PPAR a or ⁇ agonist include various known PPAR a or ⁇ agonist.
- Specific examples of PPAR ⁇ or ⁇ include, for example, WO2001 / 00 603, W099 / 62872, WO2002 / 100813, W097 / 28149, WO2004 / 02 2551, WO2001 / 79197, WO2003 / 099793, WO2005 / 105736, WO20 05/105726, WO2005 / 085235, WO2005 / 113600, WO2005 / 10575 4, WO2005 / 049606, WO2004 / 111020, WO2006 / 055187, WO2006, 084176, WO2005 / 060958, WO2005 / 097786, WO2004 / 092117, WO2005 / 037763, WO2005 / 030694, WO2005 / 016335, WO2003 / 0 74495, WO
- PPAR a or ⁇ agonistoy compounds include 2— (4-one benzoyl) phenoxy—2-methylpropionic acid 1-methylethyl ester (fenofibrate; CAS registration number) 49562- 28-9), ((4 Chloro-6-((2,3 dimethylphenol) amino) 2-Pyrimidinyl) thio) acetic acid (WY-14643; CAS Registry Number 50892- 23-4), (4 3— (4-Acetyl 3 hydroxy-1-propyl) phenoxy) propoxyphenoxy) acetic acid (L-165 041; CAS Registry Number 79558-09-1), (2-methyl-4 ((((4-methyl-2- (4 (Trifluoromethyl) phenol) 5 Thiazolyl) methyl) thio) phenoxy) acetic acid (GW-50151 6; CAS Registry Number 317318-70-0), (4 (((((2— (3 Fluoro 4 (Trifluoro 4 Romethyl) phenol) 4
- the substance is a PPAR a or ⁇ ligand so far, and a substance (compound) that activates PPAR a or ⁇ from a substance group is screened.
- PPAR o; or ⁇ agonists are known to bind to the ligand binding domain (LBD) of PPAR o; or ⁇ , respectively, to activate the receptor and to regulate the transcription of PPAR target genes.
- LBD ligand binding domain
- a screening method using LBD and the yeast GAL4 chimeric receptor and a reporter gene in order to take advantage of this property and eliminate the influence of other nuclear receptors endogenous to mammalian cells.
- Examples of the screening method include PPAR-GAL4 Atssey (reference, TM Willson et al. Journal of Medicinal Chemistry, 2000, vol. 43, No. 4, p. 528-550 and JM ⁇ ehmann et al. , The Journal of Biological Chemistry, 1995, vol.270, No.22, p.12953-12956).
- the cell used is a cell that does not endogenously express GAL4, preferably a mammalian cell.
- the reporter gene may be any gene that encodes a detectable protein or enzyme, for example, LUC (luciferase) gene, SP AP (secreted placenta-derived alkaline phosphatase) gene, CAT (chloramphee-colacetyltransferase) gene, etc. Can be mentioned.
- Preparation of the fusion protein expression vector and reporter plasmid, and introduction of the vector and plasmid into cells can be performed by the above-mentioned references or a method known per se.
- the test substance may be V, a known compound or a novel compound.
- V a known compound or a novel compound.
- a PPA based on the presence or absence of the test substance is used by a so-called reporter assembly. Examine the transcriptional activity of Ra or ⁇ . Reporter assembly can be performed by a method known per se according to the reporter gene used.
- the test substance when the reporter activity in the presence of the test substance is significantly higher than the reporter activity in the absence, the test substance has a PPAR a or ⁇ agonistic activity and Can be determined.
- the activity of the PPAR agonist used in the present invention against human PPAR a is determined by the EC value.
- the activity of the PPAR ⁇ agonist used in the present invention against human PPAR ⁇ is expressed as an EC value of 1
- Preferred! /, PPAR a or ⁇ agonist is, for example, the following general formula (I):
- ⁇ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,
- B is — CO, 1 NH—, — (CH) — S—, — (CH) — O and — O— (CH)
- group force is selected linker
- X and Y are the same or different and represent a carbon atom or a nitrogen atom
- Z represents an oxygen atom, a sulfur atom or —CH 3;
- Ar has 1 to 3 substituents and may represent an aromatic ring group that is a 5- to 6-membered ring,
- R and R are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- R represents hydrogen, a halogen atom or an alkyl group having 1 to 6 carbon atoms].
- examples of the “alkyl group having 1 to 6 carbon atoms” represented by A include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert butyl, Pentinole, isopentyl, neopentyl, tert pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1, 2 --Dimethylbutyl, 1,3 dimethylbutyl, 2,2 dimethylbutyl, 2,3 dimethylbutinole, 3,3 dimethylenobutinole, 1-ethinolevinore, 2 ethinolevinole, 1-ethinole —2-methylpropyl, 1,
- the linker represented by B is preferably 1 CO 2, 1 NH 2, 1 CH
- the aromatic ring group that is a 5- to 6-membered ring represented by Ar includes phenyl, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1 , 2, 3 Oxadiazolyl, 1, 2, 4 Oxadiazolyl, 1, 3, 4—Oxadiazolyl, Frazar, 1, 2, 3 Thiadiazolyl, 1, 2, 4 Thiadiazolyl, 1, 3, 4 Thiadiazolyl, 1, 2 , 3 triazolyl, 1, 2, 4 triazolyl, tetrazolyl, pyridyl, pyridazyl, pyrimidyl, pyrajur, triazyl and the like.
- the aromatic ring group is preferably phenyl or thiazolyl.
- Ar may have a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, carbon Examples include a phenyl group which may have a cycloalkyl group having 2 to 7 carbon atoms, an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms.
- the substituent is preferably a chlorine atom, a hydroxy group, a methyl group, a acetyl group, a 4-trifluoromethylphenol group, or a 3-fluoro-4-methylphenol group.
- examples of the “alkyl group having 1 to 6 carbon atoms” represented by R and R include examples.
- the “halogen atom” represented by R is, for example, a fluorine atom or a salt.
- Elemental atoms, bromine atoms and the like can be mentioned.
- the halogen atom is preferably a chlorine atom.
- the “alkyl group having 1 to 6 carbon atoms” represented by R is, for example, meso
- the alkyl group having 1 to 6 carbon atoms is preferably
- salts of the compound represented by the general formula (I) include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other mineral acids; formic acid, Organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, methanesulfonic acid and ethanesulfonic acid; acids with acidic amino acids such as aspartic acid and glutamic acid Examples include addition salts. These salts also include solvates thereof.
- the compound represented by the general formula (I) may have an asymmetric carbon atom or a double bond, and such a compound may have an optical isomer or a geometric isomer.
- These isomers are also included in the scope of the present invention, and can be isolated and purified by a method known per se. In the present invention, either a mixture of these isomers or an isolated isomer can be used.
- Preferred PPAR ⁇ ligands include 4- (3- (4-acetyl-3-hydroxy-2-propyl) phenoxy) propoxyphenoxyacetic acid (L-165041; CAS Registry Number 79558-09-1), (2 —Methyl-4 ((((4-methyl-2- (4- (trifluoromethyl) phenol) 5-thiazolyl) methyl) thio) phenoxy) Acetic acid (GW-501516; CAS Registry Number 317318-70-0) , (4 ((((2- (3 Fluoro-4 mono (trifluoromethyl) phenyl) 4 methyl 5 thiazolyl) methyl) thio) 2 methylphenoxy) acetic acid (GW-0742; CAS Registry Number 317318-84-6) etc. Is mentioned.
- A represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms
- B is — (CH) — S and — O— (CH) -0- (where n is 1
- X and Y are the same or different and represent a carbon atom or a nitrogen atom
- Z represents an oxygen atom, a sulfur atom or —CH 3;
- Ar has 1 to 3 substituents and may represent an aromatic ring group that is a 5- to 6-membered ring,
- R and R are the same or different and each represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
- R represents hydrogen, a halogen atom or an alkyl group having 1 to 6 carbon atoms
- the “alkyl group having 1 to 6 carbon atoms” represented by A includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert-butyl Tyl, pentinole, isopentyl, neopentyl, tert pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1 , 2-dimethylbutyl, 1,3 dimethylbutyl, 2,2 dimethylbutyl, 2,3 dimethylbutinole, 3,3 dimethylenobutinore, 1-ethinolevinole, 2 ethinolevinore, 1-ethinole —2-methylpropyl, 1, 1, Examples include 2-trifluorine
- the linker represented by B is preferably —CH—S—, —O— (CH
- the aromatic ring group that is a 5- to 6-membered ring represented by Ar includes phenol, furyl, chenyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl 1, 2, 3 oxadiazolyl, 1, 2, 4 oxadiazolyl, 1, 3, 4—oxadiazolyl, frazar, 1, 2, 3 thiadiazolyl, 1, 2, 4 thiadiazolyl, 1, 3, 4 thiadiazolyl, 1 1,2,3 triazolyl, 1,2,4 triazolyl, tetrazolyl, pyridyl, pyridazyl, pyrimidyl, pyrajur, triazyl and the like.
- the aromatic ring group is preferably phenyl or thiazolyl.
- Ar may have a substituent as a halogen atom, a hydroxy group, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, carbon Examples include a phenyl group which may have a cycloalkyl group having 2 to 7 carbon atoms, an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms.
- the substituent is preferably a chlorine atom, a hydroxy group, a methyl group, a acetyl group, a 4-trifluoromethylphenol group, or a 3-fluoro-4-methylphenol group.
- the alkyl group having 1 to 6 carbon atoms is preferably methyl.
- examples of the “halogen atom” represented by R include a fluorine atom and a salt.
- Elemental atoms, bromine atoms and the like can be mentioned.
- the halogen atom is preferably a chlorine atom.
- the “alkyl group having 1 to 6 carbon atoms” represented by R is, for example, meso
- Til ethyl, propyl, isopropyl, butyl, isobutyl, sec butyl, tert butyl, pentinole, isopentyl, neopentyl, tert pentyl, 1-methylbutyl,
- Examples thereof include butyl, 2,3 dimethylbutinole, 3,3 dimethylenobutynore, 1-ethinolevbutenole, 2 ethinolevbutenore, 1-ethinole-2-methylpropyl, 1,1,2 trimethylpropyl and the like.
- the alkyl group having 1 to 6 carbon atoms is preferably methyl.
- salts of the compound represented by the general formula (II) include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, Organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, methanesulfonic acid and ethanesulfonic acid; acids with acidic amino acids such as aspartic acid and glutamic acid Examples include addition salts. These salts also include solvates thereof.
- the compound represented by the general formula (II) may have an asymmetric carbon atom or a double bond, and an optical isomer or a geometric isomer may exist for such a compound.
- These isomers are also included in the scope of the present invention, and can be isolated and purified by a method known per se. In the present invention, either a mixture of these isomers or an isolated isomer can be used.
- the PPAR ⁇ agonist is 4- (3- (2 propyl 1-3 hydroxy 1-4 cetyl). ) Phenoxy) propoxyphenoxyacetic acid (L-165041; CAS Registry Number 79558-09-1), (2-Methyl-4 (((4-Methyl-2- (4 (Trifluoromethyl) phenol)) ) 5 thiazolyl) methyl) thio) phenoxy) acetic acid (GW-501516; CAS Registry Number 317318-70-0), (4 ((((2— (3 Fluoro 4 (trifluoromethyl) phenol) 4 methyl 5-thiazolyl) methyl) thio) 2-methylphenoxy) acetic acid (GW-0742; CAS Registry Number 317318-84-6).
- the content of the PPAR a or ⁇ Agonisuto is usually 0.000 001-1 weight 0/0, preferably [or 0.00001 to 1 weight 0/0, most preferably ⁇ or 0 0001 to 0.1% by weight.
- the promoter of the present invention may contain an arbitrary carrier in addition to the above active ingredients.
- Such carriers include, for example, solvents (eg, water, alcohol, etc.), buffers (eg, phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamate) , Epsilon aminocaproic acid, etc.), preservatives (eg, salt benzalkonium chloride, benzethonium chloride, chlorhexidine dalconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, paraoxybenzoates, edetic acid Sodium, boric acid, etc.) and isotonic agents (eg, sodium chloride, potassium salt, glycerin, mannitol, sorbitol, boric acid, glucose, propylene glycol, etc.).
- solvents eg, water, alcohol, etc.
- buffers eg, phosphate buffer, acetate buffer, bo
- the promoter of the present invention can be used in vivo or in vitro as a pharmaceutical or a test reagent.
- the promoter of the present invention When used as a test reagent, it can be used in various modes as a test reagent in the field of physiology and biochemistry.
- the promoter of the present invention promotes the growth of meibomian gland epithelial cells, and therefore causes a disease involving damage or atrophy of meibomian gland epithelial cells, and the function of meibomian gland epithelial cells decreases It is useful as a therapeutic agent for the disease that occurs.
- the disease include meibomian gland dysfunction.
- the meibomian gland epithelial cells secrete lipid components in tears, and these lipids prevent tear evaporation and stabilize the tear film, the therapeutic agent of the present invention is in tears.
- Useful for diseases associated with lipid abnormalities decrease in secretion, change in components). Examples of the disease include dry tear evaporation type dry eye.
- the promoter of the present invention is also useful for the treatment of dry eye, corneal ulcer, punctate superficial keratopathy, corneal epithelial fistula and the like.
- the promoter of the present invention promotes proliferation of corneal epithelial cells, and thus is also useful as a therapeutic agent for diseases associated with corneal epithelial cell damage (ie, wound or defect).
- the promoter of the present invention is a corneal epithelial disorder, specifically, a corneal epithelial disorder associated with an endogenous disease such as Siedalen syndrome, Stevens' Johnson syndrome, dry eye syndrome (dry eye); Corneal epithelial disorder associated with exogenous diseases such as trauma and external lens wear; useful as a therapeutic agent for corneal epithelial disorders associated with ocular allergic diseases associated with corneal lesions such as corneal ulcers, spring catarrh and atopic keratoconjunctivitis.
- the promoter of the present invention is also useful for the treatment of punctate superficial keratopathy and corneal epithelial fistula.
- the promoter of the present invention is also useful as a corneal wound healing promoter.
- the promoter of the present invention has a corneal epithelial cell proliferation promoting action and a meibomian gland epithelial cell proliferation action, thereby improving the function of tear fluid by acting directly on corneal tissue and acting on meibomian gland cells.
- it is very useful as a therapeutic agent for dry eye with enhanced tear evaporation.
- the content of the PPAR a or ⁇ Agonisuto is usually 0.000 001-1 weight 0/0, preferably [or 0.00001 to 1 weight 0/0, most preferably ⁇ or 0 0001 to 0.1% by weight.
- the administration target of the promoter or therapeutic agent of the present invention is a mammal (eg, human, mouse).
- the therapeutic agent of the present invention can be used in dosage forms such as eye drops, patches, ointments, lotions, creams, oral preparations, etc.
- any carrier for example, pharmaceutically acceptable Can be included.
- the administration route of the therapeutic agent of the present invention is not particularly limited as long as it exhibits the above-mentioned therapeutic effect, but is preferably administered locally to the eye.
- Examples of the dosage form for topical ocular administration include eye drops and eye ointments.
- a stabilizer for example, sodium bisulfite, sodium thiosulfate, sodium edetate, sodium citrate, ascorbic acid, dibutylhydroxytoluene, etc.
- Solubilizer eg glycerin, propylene glycol, macrogol, polyoxyethylene hydrogenated castor oil
- suspension Agents eg, polybulurpyrrolidone, hydroxypropylmethylcellulose, hydroxymethylcellulose, sodium carboxymethylcellulose
- emulsifiers eg, polypyrrolidone, soybean lecithin, egg yolk lecithin, polyoxyethylene hydrogenated castor oil, polysorbate 80, etc.
- Buffer for example, phosphate buffer, acetate buffer, borate buffer, carbonate buffer, citrate buffer, Tris buffer, glutamic acid, epsilon aminocaproic acid, etc.
- thickener for example, methylcellulose Water-soluble
- the therapeutic agent of the present invention is an eye drop or an eye ointment
- it may be manufactured according to a method commonly used in the pharmaceutical field, for example, the 14th revised Japanese Pharmacopoeia, General Rules for Preparations, Eye Drops, and Eye Ointments. It can be produced based on the method described in the section.
- the present invention provides a method for promoting the growth of meibomian gland epithelial cells, comprising administering an effective amount of PPARa or ⁇ agonist to a subject in need of promoting the growth of meibomian gland epithelial cells.
- the method is preferably performed for the treatment of meibomian gland dysfunction.
- the present invention provides a subject that needs to promote proliferation of corneal epithelial cells, PPAR a or
- Providing a method of promoting corneal epithelial cell proliferation comprising administering an effective amount of ⁇ agost To do.
- the method is preferably performed for the treatment of a corneal epithelial disorder.
- the present invention also provides a method for treating tear evaporation enhanced dry eye, comprising administering an effective amount of PPAR a or ⁇ agonist to a patient suffering from tear tear enhanced dry eye. provide.
- the effective amount of PPARa or ⁇ agonist cannot be generally defined depending on the type of compound, age, weight, condition, therapeutic purpose, etc. of the subject of administration, but when the promoter or therapeutic agent of the present invention is administered to humans the, PPAR alpha or ⁇ ⁇ GORE -.
- concentration of strike preferably from 0.00001 to 1 weight 0/0, most preferably from 0.0001 to 0 1 weight 0 /
- a solution containing 0 oPARo; or ⁇ agost is exemplified once to 8 times a day, 1-2 drops per eye, i.e. about 50-200 per dose.
- An effective amount can be exemplified by the amount of PPARa or ⁇ agost contained in a solution within the range of the concentration and volume that can be used.
- Corneal epithelial cells were also prepared with a rabbit eye force.
- the excised eye force was also excised from the cornea and kept in Dulbecco's phosphate buffered saline (D—PBS; Invitrogen) and transferred to a clean bench.
- D—PBS Dulbecco's phosphate buffered saline
- the following cell preparation operations were all performed aseptically.
- the isolated corneal piece was washed three times in D-PBS supplemented with 1% penicillin-streptomycin (Invitrogen) and transferred to minimum essential medium (MEM; Invitrogen).
- MEM minimum essential medium
- the corneal endothelial cells and Descemet's membrane of corneal pieces immersed in MEM are peeled off with an ophthalmic surgical knife (Alcon) and peeled off.
- the detached corneal pieces (corneal stroma and corneal epithelium) were transferred to MEM supplemented with dispase II (Roche Diagnostics) at 2.4 U / mL. This was heated at 37 ° C for 1 hour, and then the cornase pieces treated with dispase II were transferred into MEM.
- the corneal epithelium of the corneal piece immersed in MEM was peeled off with an ophthalmic surgical knife, and the corneal residue (corneal substance) was also removed.
- the detached corneal epithelial cells are collected in a 50 mL centrifuge tube together with the MEM containing the corneal epithelial cells, centrifuged at room temperature, 1,500 rpm for 5 minutes, and the supernatant is discarded. Obtained. After adding lmL trypsin-EDTA (Invitrogen) to the corneal epithelial cell layer and mixing well, the cells were heated at 37 ° C for 5 minutes to dissociate the cells.
- the culture medium was replaced with a new one every 48 hours until the test day.
- PPAR gateway WY-14643 (Calbiochem) and fenofibrate (Sigma-Aldrich)
- PPAR delta gateway L-165041 (Sigma- Aldrich)
- test substance was dissolved in ethanol (Wako Pure Chemical Industries) to a concentration 200 times the final concentration in the culture and stored at -80 ° C until just before use.
- mEGF mouse-derived epidermal growth factor
- a 96-well tissue culture culture dish (Corning) was used as a culture dish for the cell growth promotion test.
- the day before the test 50 L each of 0.01% type I collagen (Nitta gelatin) in each well of the culture dish Dispensing and coating at 4 ° C until just before the test.
- the bottom of the culture dish was washed three times with D-PBS, and this was used as a collagen-treated culture dish for the test.
- RCGM2 was added to the obtained cells so that the cell concentration was 2 ⁇ 10 5 cells ZmL, and the cells were suspended. 64 L of this cell suspension was dispensed into each well so that the cell force was 10 4 cells Zcm 2 per bottom surface area (0.32 cm 2 ) of the 96-well tissue culture culture dish treated with collagen. After cell seeding, the culture dish is 37 ° C, 5% CO, 95%
- a male Japanese white rabbit (weight approximately 1.5 kg, Kitayama Labes) was used.
- the principles of biomedical research using animals (International Guiding Principles for Biomedical Research involving Animals) were followed.
- Rabbit corneal epithelial cells were prepared using the same method as in (Test Example 1).
- test substance was dissolved in ethanol (Wako Pure Chemical Industries) to a concentration 200 times the final concentration in the culture and stored at -80 ° C until just before use.
- mEGF mouse-derived epidermal growth factor
- the culture dish was treated with collagen in the same manner as in (Test Example 1).
- RCGM2 was added to the obtained cells so that the cell concentration was 1 ⁇ 10 5 cells ZmL, and the cells were suspended.
- the number of cells per bottom area (0.32 cm 2 ) of the 96-well tissue culture culture dish treated with collagen was 2 ⁇ 10 4 cells Zcm 2 64 L was dispensed into each hole. After cell seeding, the culture dish is 37 ° C, 5% CO, 95%
- the culture supernatant in each well was removed every 48 hours after exchanging the culture medium containing the test substance, etc., and 100 L of the newly prepared culture medium was dispensed into each well. 120 hours after the first change to the culture medium containing the test substance, etc., remove the culture supernatant from each well, and then add a basal medium supplemented with 10% Cell Counting Kit-8 (DOJINDO) to each well. Dispensed at 100 / z L. After dispensing, transfer the culture dish to 37 ° C, 5% CO, 95% air, 100% humidity in an incubator at 2 o'clock
- Table 2 shows the effect of increasing the number of cells in each group.
- the cell growth in the additive-free group was taken as 100%, the cell growth in all the test substance-added groups and the positive control group was significantly (P 0.01) higher than that in the no-addition group. It was shown that From this test result, it was clarified that compounds with PPAR ⁇ action increase the number of corneal epithelial cells. [0073] [Table 2]
- Meibomian gland epithelial cells were also prepared with monkey eyelid strength. The eyelids were removed and stored in Dulbecco's phos phate buffered saline (D-PBS; Invitrogen) and transferred to a clean bench. The following cell preparation operations were all performed aseptically.
- D-PBS Dulbecco's phos phate buffered saline
- tissue treated with the enzyme After warming, place the tissue treated with the enzyme again under a stereomicroscope, and use eyelashes and eyelids.
- the connective tissue was removed and meibomian gland tissue was isolated.
- the isolated glandular tissue was supplemented with lmL trypsin-EDTA (Invitrogen) and heated at 37 ° C for 5 minutes. After warming, add 9 mL of MEM containing 10% FBS to stop the enzyme reaction, and then 5 times with a 10 mL pipette and 5 with a syringe with a 21 G needle.
- the tissue constituent cells were dispersed by repeated suction and discharge.
- the cell dispersion was applied to a nylon filter (Cell Strainer; Falcon) of 100 ⁇ m and then to 40 ⁇ m to remove the vigorous cell mass that could not be treated with the enzyme contained therein.
- the cell suspension passed through the filter was collected in a 50 mL centrifuge tube and centrifuged at room temperature, 1,500 rpm for 5 minutes.
- the cell layer containing the target cells obtained by centrifugation is added with 80 L of D-PBS containing 0.5% bovine serum albumin (BSA; Sigma-Aldrich), and the cells are sufficiently suspended.
- BSA bovine serum albumin
- 20 ⁇ L of Anti-Fibroblast Microbeads was added and allowed to stand at room temperature for 30 minutes.
- D-PBS containing 0.5% BSA was added thereto, and again subjected to centrifugation at room temperature, 1,500 rpm for 5 minutes.
- D-PBS containing 0.5% BSA was added dropwise to an LD column (Militenyi Biotec) that had been equilibrated. Next, 2 mL of column washing solution was dropped onto the LD column.
- the antibody-unlabeled target cells that had not adsorbed to the column were collected in a 50 mL centrifuge tube.
- the cells collected in the centrifuge tube were subjected to centrifugation at room temperature, 1,500 rpm for 5 minutes, and the supernatant was removed.
- 1 mL of Defined Keratinocyte- Serum Free Medium DK-SFM; Invitrogen was added to suspend the cells to prepare a meibomian gland epithelial cell suspension.
- the prepared cells were pre-coated with a type I collagen solution (Nitta gelatin) and seeded in a 3.5 cm diameter cell culture culture dish (IWAKI) supplemented with 3 mL of DK-SFM.
- the seeded cells are cultured in an incubator (SANYO) set at 37 ° C, 5% C 0, 95% air, 100% humidity.
- PPAR fenofibrate (Sigma- Aldrich)
- PPAR ⁇ agost L-165041 (Sigma- Aldrich)
- PPAR yagost troglitazone (Calbiochem)
- test substance was dissolved in ethanol (Wako Pure Chemical Industries) to a concentration 200 times the final concentration in the culture and stored at -80 ° C until just before use.
- the DK-SFM force was used as a basal medium except for the supplement attached to it, and as a positive control for confirming the cell growth promoting effect,
- the medium supplemented with supplement (basic medium + supplement) was used as instructed in the DK-SFM preparation protocol.
- a 96-well tissue culture culture dish (Corning) was used as a culture dish for the cell growth promotion test.
- 50 L of 0.01% type I collagen (Nitta gelatin) was dispensed into each well of the culture dish and coated at 4 ° C until just before the test.
- the bottom of the culture dish was washed three times with D-PBS, and this was used as a collagen-treated culture dish for the test.
- Basal medium + supplement positive control group
- Basal medium + fenofibrate final concentration: 1 ⁇ and 10 ⁇
- the culture medium 48 hours after the first culture medium exchange, the culture medium was replaced with a freshly prepared culture medium of [1] to [4] above. 48 hours later, the culture supernatant in each well was removed, and then DK-SFM supplemented with 10% Cell Counting Kit-8 (DOJINDO) in each well was dispensed at 100 / zL. After dispensing, transfer the culture dish to an incubator set to 37 ° C, 5% CO, 95% air, 100% humidity for 2 hours.
- DOJINDO 10% Cell Counting Kit-8
- Table 3 shows the effect of increasing the number of cells in each group.
- the cell growth in the non-addition group is 100%
- the P PAR aagonist fenofibrate supplemented group the PPAR delta agonist L-165041 supplemented group
- the positive control group It was shown that cell proliferation was significantly higher ( ⁇ 0.01) than that in the non-added group, and cell proliferation was enhanced.
- troglitazone, a PPAR ligand did not show a cell growth promoting effect. From this test result, it became clear that PPAR aagost and PPARR ⁇ agost increase the number of meibomian epithelial cells.
- Usagi corneal epithelial cells were prepared and cultured in the same manner as in (Test Example 1). Salmeibom gland epithelial cells were prepared and cultured in the same manner as in (Test Example 3). Human corneal epithelial cells (Kurabo) were used in an incubator set at 37 ° C, 5% CO, 95% air, 100% humidity using serum-free basic medium (EpiL ife-Kurabo) for normal human corneal epithelial cell proliferation.
- RNA of each cell force was extracted according to the conventional method of TRizol Reagent (Invitrogen).
- PCR of the PPARs gene was performed according to the standard method of Platinum PCR SuperMix (Invitrogen). PPARs primers were designed so that the PCR product was about 200 bps with reference to known human, chimpanzee, force-quizal, ushi and mouse sequences.
- PPAR a GTAGAATCTGCGGGGACAAG (sense) (SEQ ID NO: 1)
- PPAR 6 TTCCTTCCAGCAGCTACACA (sense) (SEQ ID NO: 3)
- PPAR y CTCCGTGGATCTCTCCGTAA (sense) (SEQ ID NO: 5)
- the PCR reaction is completed at 94 ° C for 2 minutes and 15 seconds, and then completed by repeating the three-step reaction at 94 ° C for 30 seconds, 55 ° C for 30 seconds, and 72 ° C for 30 seconds 35 times. It was.
- the sample after the PCR reaction was subjected to electrophoresis using a 2% agarose gel, and then the DNA separated in the gel was stained using SYBR Gold (Molecular Probes). Stained DNA was emitted on a UV transluminator and the image was stored as digital data.
- Figure 1 shows the stained DNA band after electrophoresis.
- test substance was dissolved in ethanol (Wako Pure Chemical Industries) to a concentration 200 times the final concentration in the culture and stored at -80 ° C until just before use.
- HCGS growth additive set (KURAB)
- a medium supplemented with mouse-derived epidermal growth factor (mEGF) contained in (0) was used (basal medium + lng / ml LEGF).
- HCGS growth additive set insulin, mouse-derived epidermal growth factor, Hyde mouth cortisone, transferrin, urushi. All of the pituitary extract was transferred into 4 mL of EpiLife (complete medium) supplemented and well suspended. This cell suspension was seeded in a fibronectin-coated multi-well plate (24-well, BECTON DICKINSON) so that the cell count was 3 ⁇ 4 X 10 4 cells / 500 ⁇ L / well (bottom area was 2 cm). Since 1 ⁇ 10 4 cells / cm 2 ) 0 cell seeding, the culture dish is set to 37 ° C, 5% CO, 95% air, 100% humidity
- the culture medium was replaced with 400 L of basal medium.
- Basal medium only (no addition group)
- Basal medium + mEGF final concentration: Ing / mL; positive control group
- the culture supernatant in each well was removed, and then 200 ⁇ L of basal medium supplemented with 10% Cell Counting Kit-8 (DOJINDO) was dispensed in each well. . After dispensing, transfer the culture dish into an incubator set to 37 ° C, 5% CO, 95% air, 100% humidity.
- DOJINDO 10% Cell Counting Kit-8
- the mixture was warmed for 2 hours, and 100 L of each supernatant was dispensed from the supernatant after the reaction to a 96-well tissue culture culture dish (Corning).
- the absorbance at 450 nm of the reaction solution transferred to a 96-well culture dish was measured using a microplate reader (Dainippon Sumitomo Pharma Co., Ltd.), and this was used as an indicator of cell number increase.
- Table 4 shows the effect of increasing the number of cells in each group.
- the cell growth in the additive-free group is 100%, the cell growth in all the test substance-added groups (p 0.01) and the positive control group (p 0.05) is significantly higher than that in the non-added group was shown to be enhanced. From this test result, it was clarified that P PAR ⁇ agonist increases the number of normal human corneal epithelial cells.
- PPAR ⁇ Agonist GW-501516 (Alexis), GW-0742 (Sigma- Aldrich)
- test substance was dissolved in ethanol (Wako Pure Chemical Industries) to a concentration 200 times the final concentration in the culture and stored at -80 ° C until just before use.
- a culture solution containing EpiLife (KURABO) plus insulin, hydrocortisone, and transferrin contained in the HCGS growth additive set (KURABO) (basic Medium).
- HCGS growth additive set insulin, mouse-derived epidermal growth factor, Hyde mouth cortisone, transferrin, ushiki 4 mL of all pituitary extracts Transfer to EpiLife (complete medium) and suspend well.
- This cell suspension was seeded in a 96-well tissue culture culture dish (Corning) so that the number of cells was 1.28 X 10 4 cells / 100 ⁇ L / hole (because the bottom area is 0.32 cm 2 , 4 X 10 4 cells / cm 2 ).
- culture with culture dish set to 37 ° C, 5% CO, 95% air, 100% humidity
- Table 5 shows the effect of increasing the number of cells in each group.
- the cell growth in the additive-free group was taken as 100%, the cell growth in both test substance-added groups was significantly higher than that in the additive-free group (P 0.01). From this test result, it was found that PPAR Sagonist increases the number of normal human corneal epithelial cells. [0095] [Table 5]
- test substance was dissolved in ethanol (Wako Pure Chemical Industries) to a concentration 200 times the final concentration in the culture solution and stored at -80 ° C until just before use.
- mouse-derived epidermal growth factor was added to EpiLife (KURABO) as an additive included in the HCGS augmentation additive set (KURABO).
- mEGF mouse-derived epidermal growth factor
- the culture was continued in the vessel for 24 hours, and then the culture was replaced with a culture solution containing the following test substance, 100 L each, and the culture was continued.
- the absorbance (450 nm) of each well of the culture dish was measured using a microplate reader (Dainippon Sumitomo Pharma Co., Ltd.), and this was used as an indicator of the number of cells.
- Dmrnett's multiple comparison test method is used to calculate the values of the non-addition group and each test substance addition group when the average absorbance of the non-addition group is 100%. (One side) was used. As a result of the test, a case where the risk rate was less than 5% was determined to be significant.
- Table 6 shows the effects of PPAR agonists on normal human corneal epithelial cells. From the results of this test, PPAR y agonist did not show an effect of increasing the number of corneal epithelial cells.
- Meibomian gland epithelial cells were prepared from monkey eyelids in the same manner as in Test Example 3. Use Defined keratinocyte—3 ⁇ 4erum Free Medium (DK-SFM; Invitrogen, 7 Suppl ement added according to the preparation protocol), 37 ° C, 5% CO, 95% air, 100% humidit
- the cells were cultured in an incubator (SANYO) set to y, and the culture medium was replaced with a new one every 48 hours until the cells reached subconfluence.
- SANYO incubator
- PPAR ⁇ agost L-165041 (Sigma-Aldrich) and GW-501516 (Alexis) Each test substance was added to ethanol (Nacalai Tester) to a concentration 200 times the final concentration in the culture medium. Dissolved and stored at -80 ° C until just before use.
- DK-SFM force was used as the basal medium except for the supplement attached to this, while on the other hand, as a positive control for confirming the cell growth promotion effect, A culture solution (basal medium + supplement) supplemented with supplement was used as instructed in the DK-SFM preparation protocol.
- the culture dish for the cell growth promotion test was coated with type I collagen (Nitta gelatin) in the same manner as in Test Example 3. 2) Cell culture and test substance supplementation
- salmeibom gland epithelial cells cultured until subconfluent, suspended in a cell banker (Nippon Zenyaku Kogyo Co., Ltd.) and stored frozen in liquid nitrogen were used. After freezing and storing the cells, the cells were thawed, transferred to a 50 mL centrifuge tube, and supplemented with 10 times the amount of DK-SFM. Collect the cell layer by centrifugation at 1,500 rpm for 5 minutes at room temperature, and then add the appropriate amount of DK-SFM to suspend the cells so that the resulting cell concentration is 2 ⁇ 10 6 cells ZmL. Made it cloudy.
- the culture medium was replaced with a freshly prepared culture medium of [1] to [4] above. After 48 hours, the culture solution was again replaced with a freshly prepared culture solution of [1] to [4] above. After 48 hours, the culture supernatant in each well was removed, and then 100 / zL of basal medium supplemented with 10% Cell Counting Kit-8 (DOJINDO) in each well was dispensed. After dispensing, transfer the culture dish to 37 ° C, 5% CO, 95% air, 100% humidity in an incubator at 2 o'clock
- Table 7 shows the cell proliferation promoting effect of each group.
- PPAR [delta] ⁇ GORE - is under stringent L- 165041 (10- 6 ⁇ ) ⁇ Ka ⁇ and GW- 501516 (10- 7 ⁇ ) added Caro group, also, It was shown that the cell growth in the positive control group was significantly higher than that in the non-added group. From this test result, it was clarified that PPAR ⁇ agonist increases the number of meibomian epithelial cells.
- PPAR ⁇ agost GW-501516 (Alexis Biochemicals) was used as a test substance. GW Suspension in the following base was used as ophthalmic solution so that -501516 was 0.05%. Sodium dihydrogen phosphate dihydrate 0.05 g
- the corneal epithelial repair in both eyes was completed as the test start time (0 hour), and the corneal epithelial defect area was measured 24, 38, and 48 hours later to restore corneal epithelium repair. evaluated. That is, at each time point, 10 L of 0.1% fluorescein sodium (Wako Pure Chemicals) solution is instilled into the treated eye, and immediately an anterior segment photograph of the animal is taken using a slit lamp with a conoret filter attached. The stained corneal epithelial defect area was recorded. Present The photographed image was stored in a computer as a digital image, and the area of the corneal epithelial defect portion stained with image analysis software (Image-Pr 0 Plus) was measured.
- image analysis software Image-Pr 0 Plus
- corneal epithelial defect area measured at each time point a value when the initial value was set to 100% for each individual was calculated, and this was taken as the ratio of the remaining corneal epithelial defect.
- the proportion of residual corneal epithelial defects at each time point was compared between the base ophthalmic group and the test substance ophthalmic group by t-test, and a risk rate of less than 5% was determined to be significant.
- Table 8 shows the ratio of remaining corneal epithelial defects at each time point in the base ophthalmic group and 0.05% GW-501516 ophthalmic group.
- the rate of corneal epithelial defect was shown to be significantly smaller in the 0.05% GW-501516 ophthalmic group at 24 and 38 hours after corneal epithelial replation. After 48 hours, the corneal epithelial defect disappeared in all individuals. From the results of this study, it became clear that instillation of PPAR ⁇ agonist promotes repair of the missing corneal epithelium.
- a novel meibomian gland epithelial cell proliferation promoter or corneal epithelial cell proliferation promoter is provided, and the promoter promotes the proliferation of meibomian gland epithelial cells and corneal epithelial cells.
- the therapeutic agent of the present invention is a meibomian gland dysfunction or corneal epithelial disorder. It can be used effectively to improve the treatment of diseases such as harm, tear evaporation and dry eye.
- the present invention is based on Japanese Patent Application No. 2005-342025 filed on Nov. 28, 2005, the entire contents of which are included in the present specification.
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Abstract
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Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
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CA2630816A CA2630816C (en) | 2005-11-28 | 2006-11-27 | Pharmaceutical comprising ppar agonist |
JP2007546524A JP5186217B2 (ja) | 2005-11-28 | 2006-11-27 | Pparアゴニスト含有医薬 |
KR1020087015782A KR101409705B1 (ko) | 2005-11-28 | 2006-11-27 | Ppar 아고니스트 함유 의약 |
CN200680051899.3A CN101336113B (zh) | 2005-11-28 | 2006-11-27 | 包括ppar激动剂的药物 |
EP06833405.1A EP1964575B1 (en) | 2005-11-28 | 2006-11-27 | Pharmaceutical comprising ppar agonist |
US12/085,548 US8148389B2 (en) | 2005-11-28 | 2006-11-27 | Pharmaceutical comprising PPAR agonist |
US13/406,990 US9096538B2 (en) | 2005-11-28 | 2012-02-28 | Pharmaceutical comprising PPAR agonist |
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JP2005342025 | 2005-11-28 | ||
JP2005-342025 | 2005-11-28 |
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US12/085,548 A-371-Of-International US8148389B2 (en) | 2005-11-28 | 2006-11-27 | Pharmaceutical comprising PPAR agonist |
US13/406,990 Division US9096538B2 (en) | 2005-11-28 | 2012-02-28 | Pharmaceutical comprising PPAR agonist |
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WO2007061094A1 true WO2007061094A1 (ja) | 2007-05-31 |
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US (2) | US8148389B2 (ja) |
EP (1) | EP1964575B1 (ja) |
JP (1) | JP5186217B2 (ja) |
KR (1) | KR101409705B1 (ja) |
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WO2007114315A1 (ja) * | 2006-03-30 | 2007-10-11 | Santen Pharmaceutical Co., Ltd. | 角結膜障害治療剤 |
WO2008143254A1 (ja) * | 2007-05-21 | 2008-11-27 | Senju Pharmaceutical Co., Ltd. | PPARδアゴニスト含有医薬 |
WO2009107652A1 (ja) * | 2008-02-25 | 2009-09-03 | 参天製薬株式会社 | 角膜上皮バリア機能亢進剤 |
US20100266710A1 (en) * | 2007-07-26 | 2010-10-21 | Mihran Baronian | Pharmaceutical preparations comprising electrochemically activated hypochlorite solutions |
CN102300853A (zh) * | 2008-12-01 | 2011-12-28 | 田边三菱制药株式会社 | 含有噻唑环的羧酸衍生物及其药学用途 |
JP2013525267A (ja) * | 2010-02-25 | 2013-06-20 | エスエヌユー アール&ディービー ファウンデーション | ペルオキシソーム増殖剤活性化受容体リガンドのセレナゾール誘導体、その製造方法及びその化合物の用途 |
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US7981146B2 (en) | 2006-05-15 | 2011-07-19 | Tearscience Inc. | Inner eyelid treatment for treating meibomian gland dysfunction |
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Also Published As
Publication number | Publication date |
---|---|
US8148389B2 (en) | 2012-04-03 |
US20120220612A1 (en) | 2012-08-30 |
JPWO2007061094A1 (ja) | 2009-05-07 |
US9096538B2 (en) | 2015-08-04 |
CA2630816C (en) | 2014-08-12 |
US20090306111A1 (en) | 2009-12-10 |
EP1964575B1 (en) | 2015-09-23 |
EP1964575A4 (en) | 2010-08-04 |
EP1964575A1 (en) | 2008-09-03 |
CN101336113B (zh) | 2015-07-29 |
KR20080080595A (ko) | 2008-09-04 |
CA2630816A1 (en) | 2007-05-31 |
JP5186217B2 (ja) | 2013-04-17 |
CN101336113A (zh) | 2008-12-31 |
KR101409705B1 (ko) | 2014-07-14 |
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