WO2021215836A1 - Composition pharmaceutique destinée au traitement ou à la prévention de maladies oculaires comprenant un dérivé de verbénone - Google Patents

Composition pharmaceutique destinée au traitement ou à la prévention de maladies oculaires comprenant un dérivé de verbénone Download PDF

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WO2021215836A1
WO2021215836A1 PCT/KR2021/005067 KR2021005067W WO2021215836A1 WO 2021215836 A1 WO2021215836 A1 WO 2021215836A1 KR 2021005067 W KR2021005067 W KR 2021005067W WO 2021215836 A1 WO2021215836 A1 WO 2021215836A1
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hept
dimethyl
bicyclo
group
styryl
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PCT/KR2021/005067
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Korean (ko)
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주청
이동원
정성
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신풍제약주식회사
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    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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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  • the present invention relates to a pharmaceutical composition for the treatment or prevention of ocular diseases comprising a berbenone derivative, and more particularly, acts as a CD147 inhibitor to attenuate pathological fibrosis in the cornea of mice with corneal burns, and through MMP-9 activation
  • a pharmaceutical composition for prevention By inhibiting corneal opacity and related myofibroblast differentiation, it suppresses not only corneal burns but also eye damage and inflammation, such as conjunctivitis or dry eye syndrome, and relieves symptoms to treat and prevent eye diseases, including berbenone derivatives.
  • Treatment or It relates to a pharmaceutical composition for prevention.
  • Corneal and conjunctival diseases are caused by defects in the surface of the corneal epithelium. Causes include dry eye syndrome, various corneal conjunctivitis, allergies and pathogenic factors such as infections of microorganisms such as viruses, bacteria, and fungi, chemical factors such as cytotoxicity by chemicals and corrosion by acids and bases, dryness of the ocular surface, contact This may include external substances such as lenses and physical factors such as damage caused by hot water. It has been reported that preservatives such as benzalkonium chloride and chlorobutanol and ophthalmic preparations such as aminoglycoside antibiotics, non-steroidal anti-inflammatory drugs, IDU, and pimaricin contained in the ophthalmic composition cause lesions of the corneal epithelium.
  • preservatives such as benzalkonium chloride and chlorobutanol and ophthalmic preparations such as aminoglycoside antibiotics, non-steroidal anti-inflammatory drugs, IDU, and pimaricin contained in the ophthal
  • Corneal disease refers to any disease that causes damage to transparent vision by damaging the cornea, which plays a protective role to protect the eye and refracts and transmits light entering the eye to reach the retina.
  • Corneal diseases include keratitis dry (dry eye syndrome), keratitis, corneal abnormality, corneal degeneration, congenital corneal dystrophy, corneal erosion, and corneal opacity.
  • DED dry eye syndrome
  • a disorder of the tear film due to tear deficiency or excessive evaporation it is associated with a symptom of discomfort in the eye that causes damage to the ocular surface between the eyelids.
  • Dry eye syndrome is a multifactorial disease of the tear and ocular surface that causes potential damage to the ocular surface with symptoms of discomfort, visual impairment and tear film instability, accompanied by increased osmotic pressure of the tear film and inflammation of the ocular surface. There are various factors that cause dry eye syndrome.
  • corneal opacity is a common clinical outcome that impairs visual function by interfering with light transmission of the cornea and is a leading cause of blindness worldwide (Oliva, MS et al., Indian J ophthalmol 2012 , 60 , 423). -427; Dohlman, TH et al., Semin Ophthalmol 2019 , 34 , 205-210).
  • the corneal fibrosis response to corneal damage caused by various causes, including injury, surgery, infection, and chemical burns often causes severe pathological corneal opacity, greatly affecting the patient's quality of life (Dohlman, et al. TH et al., Semin Ophthalmol 2019 , 34 , 205-210). Therefore, there is a need to develop a therapeutic agent for corneal fibrosis that can prevent corneal opacity or return the existing fibrous tissue to a transparent cornea.
  • Corneal fibrosis following corneal damage is closely related to the activation of corneal myofibroblasts that occur continuously in the damaged cornea (Sivak, JM et al., Prog Retin Eye Res 2002 , 21 , 1-14; Gabison, EE et al. al., Prog Retin Eye Res 2009 , 28 , 19-33; Wilson, SE, Exp Eye Res 2012 , 99 , 78-88; Hassell, JR et al., Exp Eye Res 2010 , 91 , 326-335). After corneal injury, corneal fibroblasts are activated and differentiated into myofibroblasts (Wilson, SE, Exp Eye Res 2012 , 99 , 78-88).
  • myofibrils can produce an unorganized fibrous extracellular matrix (ECM), which contributes to a decrease in the refractory index while greatly increasing light scattering (Boote, et al. C. et al., IOVS 2012 , 53 , 2786-2795; Massoudi, D. et al., Cell Tissue Res 2016 , 363 , 337-349; Kivanany, PB et al., Sci Rep 2018 , 8 , 12580).
  • ECM extracellular extracellular matrix
  • CD147 Differentiation cluster 147
  • MMP extracellular matrix metalloproteinase
  • EMMPRIN extracellular matrix metalloproteinase inducer
  • TGF- ⁇ tumor growth factor- ⁇
  • CD147 induces MMP-9, which destroys the epithelial basement membrane, promoting epithelial-stromal cell interaction and penetration of myofibroblast-inducing factors, eventually accelerating myofibroblast differentiation (Huet, E. et al., Am J Pathol). 2011 , 179 , 1278-1286; Mauris, J. et al., J Cell Sci 2014 , 127 , 3141-3148). Therefore, CD147 and thus MMP-9 activation could be a potential therapeutic target for attenuation of corneal fibrosis.
  • chondroitin sulfate, glutathione, hyaluronic acid, fibronectin, EGF, etc. are administered to treat corneal and conjunctival lesions, or artificial tears are administered for the purpose of replenishing the tears, but there is a problem that the effect of treatment is insufficient.
  • the berbenone derivative compound acts as a CD147 inhibitor to attenuate pathological fibrosis in the cornea of rats burned with alkali, and corneal opacity and related complications through MMP-9 activation.
  • myofibroblast differentiation By inhibiting myofibroblast differentiation, it was confirmed that it is possible to treat and prevent eye diseases by suppressing eye damage and inflammation such as conjunctivitis, corneal burns or dry eye syndrome, and alleviating symptoms, and thus completed the present invention.
  • the present invention provides a pharmaceutical composition for the treatment or prevention of eye diseases comprising the berbenone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C 1-3 alkyl group, a C 1-3 alkoxy group, an amino group, and a C 1-3 alkylamine group, C 1-3
  • X, Y and Z are each independently a carbon atom or an N, O or S atom;
  • the present invention also provides a health functional food for preventing or improving eye diseases, comprising the berbenone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides an eye comprising the step of administering to a subject a pharmaceutical composition for the treatment or prevention of eye diseases comprising the berbenone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient
  • a method for treating or preventing a disease is provided.
  • the present invention also provides the use of a composition for treating or preventing ocular diseases comprising the berbenone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a use in the manufacture of a medicament for the treatment or prevention of eye diseases, comprising the berbenone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • FIG. 1 is a view showing that SP-8356 inhibits alkaline corneal opacity and corneal thickness increase 2 weeks after alkali burn according to an embodiment of the present invention.
  • A Representative image of corneal haze. Photograph of alkaline burn whole corneal sections stained with H & E (SP-8356; 0.933 mM SP-8356 in 0.9% saline, PA; 1% prednisolone acetate).
  • B Quantitative analysis of corneal opacity.
  • C Quantitative analysis of corneal thickness in five regions of interest.
  • FIG. 2 is a view showing that SP-1154 inhibits alkaline corneal opacity after 2 weeks of alkaline burns according to an embodiment of the present invention.
  • SP-8356 was used as a suspension because it does not dissolve well in saline, but in the examples from FIG. -8356 1154) was used.
  • the valine ester (SP-8356 1154) of SP-8356, which is a prodrug form of SP-8356, is converted to SP-8356 very quickly and dissolved in hyaluronic acid, which has high water solubility and is viscous. did.
  • A Representative images of corneal haze (HA; 0.1% hyaluronic acid, SP-1154/HA; 0.1% hyaluronic acid, 0.05% SP-1154 dissolved in PA; 1% prednisolone acetate).
  • B Quantitative analysis of corneal opacity.
  • FIG. 3 is a diagram showing that SP-1154 inhibits the corneal myofibroblast population 2 weeks after alkali burn according to an embodiment of the present invention.
  • A Representative images of myofibroblast populations. Alkaline burnt whole corneal sections were mounted flat and stained with H&E and anti- ⁇ SMA antibodies.
  • B Quantitative analysis of ⁇ SMA in the whole cornea.
  • C Quantitative analysis of relative mRNA levels of ⁇ SMA.
  • FIG. 4 is a diagram showing that SP-1154 inhibits MMP activity 2 weeks after alkali burn according to an embodiment of the present invention.
  • A Representative images of MMP activity visualized by in situ zymography. Scale bar, 100 ⁇ m (magnification, x 200).
  • B Representative image of MMP-9 gelatin acrylamide gel zymography.
  • C Quantitative analysis of the relative levels of MMP-9 activity in whole corneal lysates.
  • 5 is a view showing the evaluation of the drug efficacy of SP-1154 through fluorescein staining of the ocular surface of dry eye according to an embodiment of the present invention.
  • FIG. 6 is a view confirming the angiogenesis inhibitory ability of SP-1154 in an animal model for dry eyes according to an embodiment of the present invention.
  • FIG. 7 is a view confirming the ability of SP-1154 to inhibit inflammatory cell infiltration in a dry eye animal model according to an embodiment of the present invention.
  • corneal fibrotic response to corneal damage often leads to severe corneal opacification, resulting in severe visual impairment or blindness.
  • the persistence of corneal opacity is highly dependent on the activity of corneal myofibroblasts.
  • Myofibroblasts promote opacification by synthesizing an opaque and disorganized extracellular matrix (ECM).
  • ECM extracellular matrix
  • Differentiation cluster 147 CD147
  • CD147 a member of the immunoglobulin superfamily, is known to play an important role in the process of fibroblast-to-myofibroblast differentiation in damaged corneas, and thus may be an effective target for the treatment of corneal opacities.
  • berbenone derivatives (1 S ,5 R )-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-ene- 2-one ((1 S ,5 R )-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one), SP-8356 ) was confirmed to have an efficacy in treating corneal fibrosis by inhibiting CD147.
  • SP-8356 significantly reduced corneal opacity and fibrosis in alkali-burned corneas. Specifically, SP-8356 inhibits both ECM-related products such as ⁇ -smooth muscle actin ( ⁇ -SMA) and matrix-metalloproteinase-9 (MMP-9), which express myofibroblasts, and collagen types III and IV. suppressed. Similar to SP-8356, topical corticosteroids (prednisolone acetate, PA) also reduced ECM-related products and opacification. However, it was confirmed that prednisolone acetate did not reduce the number of ⁇ -SMA-positive corneal myofibroblasts.
  • prednisolone acetate did not reduce the number of ⁇ -SMA-positive corneal myofibroblasts.
  • the synthetic small molecule drug SP-8356 ((1 S ,5 R )4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one ) directly binds to CD147 to inhibit neointimal hyperplasia and stabilize plaque vulnerability in animal models through inhibition of MMP-9 activity (Pahk, K. et al., J Transl Med 2019 , 17 , 274). ; Pahk, K. et al., Int J Mol Sci 2019 , 21 , 95) having an antitumor effect through inhibition of the CD147/MMP-9 pathway (Mander, S. et al., Sci Rep 2019 , 9) , 6595), the inhibitory pharmacological effect of SP-8356 on corneal fibrosis, which is known to be mediated by CD147/MMP-9, was confirmed.
  • DED dry eye syndrome
  • the present invention in one aspect, relates to a pharmaceutical composition for the treatment or prevention of eye diseases comprising the berbenone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a C 1-3 alkyl group, a C 1-3 alkoxy group, an amino group, and a C 1 . -3 alkylamine group, C 1-3
  • X, Y and Z are each independently a carbon atom or an N, O or S atom;
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, an ethyl group, a methoxy group, an ethoxy group,
  • R 1 , R 2 , R 3 , R 4 , and R 5 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, a methyl group, a methoxy group, a phenyl group, a pyrrole group,
  • the berbenone derivative is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe
  • At least one may be selected from the group consisting of ) vinyl)-3-methoxy-1,2-phenylene bis(2-amino-3-methylbutanoate)-2-hydrochloride (6), preferably (1 S ,5 R )-4-(3,4-dihydroxy-5-methoxystyryl)-6,6-dimethylbicyclo[3.1.1]hept-3-en-2-one (3f ) or ( 2S ,2 ′S )-5-((E)-2-((1R,5S)-6,6-dimethyl-4-oxobicyclo[3.1.1]hept-2-ene-2 -yl)vinyl)-3-methoxy-1,2-phenylene bis(2-amino-3-methylbutanoate)-2-hydrochloride
  • the ocular disease may be a corneal disease or conjunctival disease, and the ocular disease may be selected from the group consisting of conjunctivitis, corneal burns, dry eye syndrome, ocular hyperemia, corneal neovascularization and keratitis, and the ocular disease may be non-infectious.
  • the pharmaceutical composition may be an ocular external formulation.
  • treatment means that the symptoms of ocular disease are improved or changed advantageously by administration of a composition comprising the berbenone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient. refers to all actions
  • prevention refers to a method of inhibiting or delaying symptoms of eye diseases by administering a composition comprising a berbenone derivative represented by Formula 1 according to the present invention or a pharmaceutically acceptable salt thereof as an active ingredient. say all actions.
  • prodrug refers to a derivative of a drug molecule that requires conversion to a parent drug through enzymes or hydrolysis in order to release an active drug in and outside the body. Prodrugs are frequently, but not necessarily, pharmaceutically inactive while the parent drug is being converted.
  • the compounds of the present invention represented by Formula 1 may be prepared as pharmaceutically acceptable salts and solvates according to conventional methods in the art.
  • an acid addition salt formed with a pharmaceutically acceptable free acid is useful.
  • Acid addition salts are prepared by conventional methods, for example by dissolving the compound in an aqueous solution of excess acid and precipitating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal molar amounts of compound and acid or alcohol (eg glycol monomethyl ether) in water may be heated to dryness, followed by evaporation of the mixture, or the precipitated salt may be filtered off with suction.
  • acid or alcohol eg glycol monomethyl ether
  • organic acids and inorganic acids can be used as free acids, hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, tartaric acid, etc. can be used as inorganic acids, and methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, Citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid ( gluconic acid), galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid and the like can be used.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • the alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and then evaporating and drying the filtrate.
  • it is pharmaceutically suitable to prepare a sodium, potassium or calcium salt in particular as the metal salt, and the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).
  • a suitable silver salt eg, silver nitrate
  • the pharmaceutically acceptable salts of the compound having the structure of Formula 1 include salts of acidic or basic groups that may be present in the compound having the structure of Formula 1, unless otherwise indicated.
  • pharmaceutically acceptable salts include sodium, calcium and potassium salts of hydroxy groups
  • other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen
  • phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) are salts of phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate), and methods or processes for preparing salts known in the art can be manufactured through
  • composition used in the present invention means one prepared for the purpose of preventing or treating a disease, and may be formulated in various forms according to each conventional method.
  • it can be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, etc., and can be used in the form of external preparations, suppositories, and sterile injection solutions.
  • it can be used in a form suitable for eye drop administration, for example, formulated as eye drops, creams, ointments, gels or lotions.
  • the route of administration of the pharmaceutical composition according to the present invention is, but not limited to, oral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, topical, sublingual, instillation or rectal. Oral or parenteral administration is preferred.
  • parenteral includes subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrabursar, intrasternal, intrathecal, eye drop, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical composition of the present invention may also be administered in the form of a suppository for rectal administration.
  • the pharmaceutical composition of the present invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • commonly used carriers include lactose and corn starch.
  • Lubricants such as magnesium stearate are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • the pharmaceutical composition of the present invention varies depending on several factors including the activity of the specific compound used, age, weight, general health, sex, diet, administration time, administration route, excretion rate, drug formulation, and the severity of the specific disease to be prevented or treated can change to
  • the pharmaceutical composition is formulated or combined with one or more agents selected from the group consisting of calcium channel blockers, antioxidants, glutamate antagonists, anticoagulants, antihypertensive agents, antithrombotic agents, antihistamines, anti-inflammatory analgesics, anticancer agents and antibiotics.
  • agents selected from the group consisting of calcium channel blockers, antioxidants, glutamate antagonists, anticoagulants, antihypertensive agents, antithrombotic agents, antihistamines, anti-inflammatory analgesics, anticancer agents and antibiotics.
  • the present invention relates to a health functional food for preventing or improving eye diseases, comprising the berbenone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the functional food of the present invention can be used in various ways, such as pharmaceuticals, foods and beverages for preventing inflammation.
  • the functional food of the present invention includes, for example, various foods, candy, chocolate, beverage, gum, tea, vitamin complex, health supplement, and the like, and may be used in powder, granule, tablet, capsule or beverage form.
  • composition comprising the compound according to the present invention is formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods.
  • oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., external preparations, suppositories, and sterile injection solutions, respectively, according to conventional methods.
  • Carriers, excipients and diluents that may be used in the formulation include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, magnesium stearate and mineral oil.
  • diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one or more excipients in the compound at least cotton, starch, calcium carbonate, sucrose Or it is prepared by mixing lactose, gelatin, etc.
  • lubricants such as magnesium stearate talc are also used.
  • Liquid formulations for oral use include suspensions, solutions, emulsions, syrups, etc.
  • various excipients for example, wetting agents, sweeteners, fragrances, preservatives, etc. may be included. .
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories.
  • Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
  • injectable esters such as ethyl oleate.
  • As the base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
  • the preferred dosage of the compound of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the drug form, the route and duration of administration, but may be appropriately selected by those skilled in the art. However, for a desirable effect, the compound is preferably administered at 0.01 mg/kg to 10 g/kg per day, preferably 1 mg/kg to 1 g/kg. Administration may be administered once a day, or may be administered in several divided doses. Therefore, the above dosage does not limit the scope of the present invention in any way.
  • it comprises the step of administering to the eye of an individual a pharmaceutical composition for the treatment or prevention of eye diseases comprising the berbenone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient
  • a pharmaceutical composition for the treatment or prevention of eye diseases comprising the berbenone derivative represented by Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient
  • Reagent grade (1 S )-(-)-verbenone, 3,4-dihydroxy-5-methoxybenzaldehyde, methylchloromethylether (MOM-Cl), diisopropylethylamine ; DIPEA), potassium hydroxide (KOH), and sodium methoxide (NaOCH3) were purchased commercially, and all reagents and solvents were purchased and used in high purity. Additional purification process except dichloromethane distilled with calcium hydroxide It was used directly without, and unless otherwise stated, the reaction was carried out in a vacuum-flame dried glassware under a dry nitrogen atmosphere.
  • TLC Thin-layer chromatography
  • UV Merck silica gel 60 F 254
  • column chromatography uses silica gel (E. Merck silica gel, 70-230, 230-400mesh). was used.
  • FBS Fetal bovine serum
  • a compound of Formula 3f was prepared according to Scheme 1 below.
  • (1S)-(-)-verbenone 1 380 mg and 3-methyl 620 mg of oxy-4,5-bis(methoxymethoxy)benzaldehyde was added to 6.2 mL of MeOH, 270 mg of KOH was added, stirred at 60° C., and cooled to room temperature. A small amount of water was added and the organic layer was separated.
  • the prodrug SP-1154 was prepared according to Scheme 2 below.
  • Example 1 Effect of berbenone derivatives on corneal opacity after corneal burns
  • mice 6-week-old male Sprague-Dawley (SD) mice were obtained from Orient Bio (Seongnam, Korea). All rats were housed on a 12 h light-dark cycle with free access to water and food. All experimental protocols were approved by the Animal Experiment and Use Committee (Approval No. KOREA-2018-0030), College of Medicine, Korea University.
  • CAI Corneal alkali injury
  • mice After 2 weeks of acclimatization, 8-week-old rats suffered corneal alkali burns as previously described (50). Briefly, rats were anesthetized with 3.5% isoflurane in a 2:1 N 2 O/O 2 mixture. The gas mixture was maintained in the anesthesia chamber via inhalation of rats through a 2.5% nasal horn. A 3 mm diameter round filter paper dipped in 1N NaOH was attached to the center of the cornea for 1 minute. The cornea was then rinsed with 30 mL of 0.9% saline. All CAIs were induced in the right eye.
  • mice After alkaline burn induction, to prevent unintentional infection, 50 ⁇ L of antibiotics (5 mg/mL levofloxacin, Santen; Osaka, Japan) were topically administered to all mice twice a day until euthanized. Rats were randomly divided into 4 groups. The saline group was treated with 50 ⁇ L of 0.9% saline twice a day, and the HA group was treated with 50 ⁇ L of 0.1% sodium hyaluronate (Xenobella 0.1 SD, Chong Kun Dang, Seoul, Korea) twice a day.
  • antibiotics 5 mg/mL levofloxacin, Santen; Osaka, Japan
  • Rats were randomly divided into 4 groups. The saline group was treated with 50 ⁇ L of 0.9% saline twice a day, and the HA group was treated with 50 ⁇ L of 0.1% sodium hyaluronate (Xenobella 0.1 SD, Chong Kun Dang, Seoul, Korea) twice a day.
  • the SP-8356/HA group received topical treatment with 50 ⁇ L of 0.05% (w/v,) SP-8356 dissolved in 0.1% sodium hyaluronate twice a day, while the PA group received 50 ⁇ L of 1% prednisolone acetate (prednisolone acetate, Pred Forte, Allergan; Dublin, Ireland) was applied topically twice a day.
  • 1X PBS 137 mM NaCl, 2.7 mM KCl, 4.3 mM Na 2 HPO 4 , 1.4 mM KH 2 PO 4 , pH 7.2, Bioseg, Seongnam, 0.2X phosphate buffered saline (PBS) buffer prepared from Korea
  • PBS phosphate buffered saline
  • the 0.2X PBS group was topically treated with 50 ⁇ L of 0.2X PBS twice a day.
  • the SP-8356 group was treated topically with 50 ⁇ L of 0.05% (w/v) SP-8356 dissolved in 0.2X PBS twice daily.
  • mice were euthanized 5 days after CAI. Rats were euthanized 2 weeks after CAI for evaluation of corneal opacity and fibrosis by alkali burn.
  • the opacity rating of the cornea was determined using the scoring system of Sonoda and Streilein (51), and opacity scores between 0 and +4 were rated as previously described (52). Two independent investigators (CJ and KP) graded the opacity in a blind manner.
  • mice were humanely sacrificed using a CO 2 chamber and the eyes of the mice were dissected for corneal tissue isolation.
  • the cornea was fixed with stirring in 4% para-formaldehyde (PFA, Biosesang) for 12 hours at 4°C, washed with 1X PBS overnight at 4°C with stirring, and 4 in 0.1M PB buffer in 30% sucrose for 12 hours. It was cryoprotected with stirring at °C.
  • the cornea was embedded in an optimal cutting temperature (OCT) compound (Scigen Scientific; Gardena, CA, USA) and stored at -80°C until cryosection was performed.
  • OCT optimal cutting temperature
  • Transverse continuous sections 8 ⁇ m thick were prepared with a cryostat (cryostat, CM3050S, Leica; Wetzlar, Germany) and collected on silane-coated glass slides (5116-20F, Muto Pure Chemicals, Tokyo, Japan). Samples were stored at -20°C until IHC and hematoxylin and eosin (H&E) staining was performed.
  • H&E staining of frozen corneal cryosections was performed according to the following procedure: (i) corneal samples were dried at room temperature for 1 hour and washed with 1X PBS, (ii) washed with distilled water, (iii) hematoxylin solution (Harris) variation) for 2 min and staining, (iv) washing 10 times with distilled water, (v) immersion and backstaining for 2 min in eosin solution, (vi) washing 10 times with distilled water, (vii) 10 sec with 50% ethanol (viii) wash and dehydrate in 70% ethanol for 10 seconds, (ix) wash and dehydrate in 90% ethanol for 10 seconds, (x) wash and dehydrate twice in 100% ethanol for 10 seconds, ( xi) immersion in xylene for 10 seconds, and (xii) mounted with Canadian balsam (Canada balsam, Junsei, Tokyo, Japan) dissolved in xylene. All H&E staining images were taken with a Zeiss Axio
  • IHC of frozen corneal cryosections was performed by the following procedure: (i) corneal samples were dried at room temperature for 1 hour and washed twice with 1X PBS, (ii) 5% normal goat serum in 1X PBS. , NGS) (Vector Laboratories; Burlingame, CA, USA) and 0.1% Triton X-100 (Sigma-Aldrich) in blocking buffer for 1 h at room temperature, (iii) incubated overnight in primary antibody solution at 4 °C.
  • the primary antibodies used for IHC were anti- ⁇ -SMA (1:400 dilution, ab7817, Abcam), anti-collagen type III (anti-collagen type III, 1:400 dilution, ab7778, Abcam), anti-collagen type IV (1:400 dilution, ab6586, Abcam) and anti-TGF- ⁇ 1 (1:500 dilution, ab92486, Abcam) antibodies. All fluorescence images were taken with a Zeiss Axio Scan.Z1 (Carl Zeiss; Jena, Germany).
  • Flat corneal IHC of the cornea was performed by the following procedure: (i) washing the fixed cornea with 1X PBS with stirring at 4°C for 24 hours, (ii) 1% Triton X-100 in 1X PBS (1% PBST) (Sigma-Aldrich) and incubated at 4°C with stirring for 24 h, (iii) immersed in 5% NGS-based blocking buffer at 4°C with stirring for 24 h, (iv) fluorescence with stirring at 4°C for 48 h.
  • Bright field images of the flat cornea were captured to evaluate the opaque area of the entire cornea.
  • an overhead projector (OHP) film printed in black with a laser printer was placed under the slide glass.
  • a 3 mm depth of the area was imaged at 40 ⁇ magnification at 40 ⁇ m spacing.
  • Images were captured with an Edge 3D microscope (Edge-3D; Paia, HI, USA) and mounted on a D5500 digital camera (Nikon; Tokyo, Japan).
  • a set of corneal images were staked out using Edge panfocal software 2.7.4 (Edge-3D) and vertically merged into a single image.
  • Areas of opaque regions were graded according to the following procedure: (i) dividing the planar-mounted cornea into 5 regions of interest (ROI, quadrants and center), and (ii) areas of opaque regions were calculated based on the visual scoring system. Rating (0; clear, printed black pattern detail visible through the cornea, borders of empty pores not scattered by the cornea; 1+, area less than 30% opaque; 2+, area greater than 30% This opacity) (iii) 5 ROI scores were summed and used as a representative score of each CAI rat. Two independent investigators (CJ and KP) assessed the rating in a blind manner.
  • CJ and KP assessed the rating in a blind manner.
  • Unfixed corneas were prepared for cryosectioning. Briefly, unfixed corneas embedded in O.C.T compounds (Scigen Scientific) were frozen into containers filled with isopentane immersed in liquid nitrogen. Transverse continuous sections of 8 ⁇ m thickness were prepared with a cryostat (CM3050S, Leica) and collected on silane-coated glass slides (5116-20F, Muto Pure Chemicals) within 1 week after harvest.
  • In situ MMP zymography was performed according to the following procedure: (i) corneal sections were dried at room temperature for 1 hour, (ii) DQ gelatin fluorescein conjugate diluted 1:50 with zymogram development buffer ( Prepare a matrix containing DQ gelatin fluorescein conjugate, Invitrogen), (iii) rehydrate the corneal sections, (iv) incubate in the matrix for 12 hours in a humidified chamber at 37°C, (v) wash 3 times with 1X PBS , (vi) mounted on mounting medium (DAKO). All gelatinase activity images were taken with a Zeiss Axio Scan.Z1 (Carl Zeiss).
  • Corneas from sacrificed rats were harvested in ice-cold 1X PBS and lysed in RIPA buffer (Thermo Fisher Scientific; Waltham, MA, USA) containing a protease inhibitor (Gendepot; Katy, TX, USA).
  • the protein concentration of the corneal lysate was quantified using a BCA protein assay kit (Thermo Fisher Scientific). Lysates containing 20 ⁇ g of protein were mixed with SDS sample buffer and heated at 99° C. for 5 minutes.
  • Lysates of non-fixed corneas were prepared in the same manner as described in the Western blot method. Lysates containing 10 ⁇ g of protein were mixed with non-reducing loading buffer and then transferred to a 10% gelatin acrylamide gel without heating. The gel contained 1 mg/ml gelatin powder (JT Baker Chemical Co.; Phillipsburg, NJ, USA) and 0.4% glycerol (Sigma-Aldrich) in a 10% SDS-PAGE gel of a conventional composition. Corneal lysates were separated by electrophoresis at 200 V for 100 min.
  • MMP-9 recombinant protein (ab168863, Abcam) was loaded.
  • the gel was washed with zymogram renaturing buffer (Invitrogen) at room temperature while stirring twice for 1 hour.
  • the gel was immersed in zymogram developing buffer (Invitrogen) for 30 minutes at room temperature while shaking. The gel was then incubated in fresh zymogram development buffer for 48 hours at 37°C with stirring.
  • the fully developed gel was stained with a colloidal blue staining kit (Invitrogen). Images of the stained gels were captured with a Bio 5000 scanner (Microtek). Quantification of MMP-9 activity was analyzed with ImageJ open source software (version 1.45s, NIH).
  • RNA of CAI cornea was extracted with TRIzol (Invitrogen). Briefly, each cornea was immersed in 40 ⁇ L of ice-cold TRIzol and triturated with a disposable homogenizer (Biomasher II, 890863, LMS Co.; Tokyo, Japan). RNA concentration was measured with Nanodrop TM 2000 (Thermo Fisher Scientific), and 1 ⁇ g of RNA template was used for cDNA synthesis. Generation of cDNA was performed using a reverse transcription reaction kit (iScript® cDNA synthesis kit, Bio-Rad; Hercules, CA, USA).
  • iScript® cDNA synthesis kit Bio-Rad; Hercules, CA, USA.
  • sequences of the primers are as follows: ⁇ -SMA (5'-GCTATTCAGGCTGTGCTGTC-3' and 5'-GTTGTGAGTCACGCCATCTC-3'), GAPDH (5'-AAGCTGTGGGCAAGGTCAT-3' and 5'-TTTCTCCAGGCGGCATGTCA-3') and TGF- ⁇ 1 (5′-GGCTACCATGCCAACTTCTG-3′ and 5′-CGTAGTAGACGATGGGCAGT-3′). mRNA levels were normalized to those of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) as previously reported (53).
  • GAPDH 5'-AAGCTGTGGGCAAGGTCAT-3' and 5'-TTTCTCCAGGCGGCATGTCA-3'
  • TGF- ⁇ 1 5′-GGCTACCATGCCAACTTCTG-3′ and 5′-CGTAGTAGACGATGGGCAGT-3′.
  • SP-8356 was used as a suspension because it does not dissolve well in salt (saline), and although its medicinal effect is weak, it is significant (FIG. 1).
  • valine ester (SP-8356 1154) of SP-8356 was converted to SP-8356 very quickly and dissolved in 0.1% hyaluronic acid with high water solubility and viscosity. Soluble SP-8356 (SP1154) is more effective than SP-8356 administered in suspension. Both SP-1154/HA and prednisolone acetate (PA) significantly attenuated the severity of corneal opacity in the CAI rat model compared to the saline-treated control group ( FIGS. 2A and 2B ).
  • ⁇ -SMA alpha-smooth muscle actin
  • FIGS. 3A and 3B flat mount IHC images showed that SP-1154/HA significantly downregulates the area of the ⁇ -SMA(+) region in the entire cornea.
  • the mRNA level of ⁇ -SMA in the whole corneal lysate was also significantly decreased in the cornea treated with SP-1154/HA ( FIG. 3C ).
  • Treatment with HA alone reduced the expression of ⁇ -SMA in the alkali-damaged cornea, but the combined treatment with SP-1154 reduced both the mRNA levels of ⁇ -SMA protein and ⁇ -SMA ( FIG. 3 ).
  • treatment with SP-1154 alone significantly reduced the mRNA level of ⁇ -SMA in the alkali-damaged cornea.
  • PA did not show any notable effect on significantly reducing ⁇ -SMA expression in the corneal matrix or the mRNA level of ⁇ -SMA in total corneal lysate ( FIG. 3 ).
  • CD147 plays an important role in the fibrotic process in response to corneal injury (Huet, E. et al., FASEB J 2008 , 22 , 1144-1154; Girard, MT et al., J Cell Sci 1993 , 104 , 1001- 1011; Fini, ME, Prog Retin Eye Res 1999 , 18 , 529-551; Fini, ME et al., Cornea 2005 , 24 ( Suppl. 1) , S2-S11; Huet, E. et al., Connect Tissue Res 2008 , 49 , 175-179). It was clearly found that the CD147 inhibitor SP-8356 significantly reduced corneal fibrosis and haze by inhibiting myofibroblast population and MMP-9 activity in alkaline burn cornea.
  • Fibrosis of the damaged cornea depends on direct cell-cell interactions between corneal cells (Gabison, EE et al., Prog Retin Eye Res 2009 , 28 , 19-33).
  • Several previous studies have reported that CD147 is involved in this direct cell-cell interaction through contact-dependent (ie, juxtacrine) signaling between corneal cells (Gabison, EE et al., Prog Retin Eye Res 2009 , 28 , 19).
  • contact-dependent (ie, juxtacrine) signaling between corneal cells Gabison, EE et al., Prog Retin Eye Res 2009 , 28 , 19).
  • Wilson SE Exp Eye Res 2012 , 99 , 78-88.
  • CD147 expression and thus MMP activation are upregulated in corneal fibroblasts after contact with epithelial cells (Gabison, EE et al., Am J Pathol 2005 , 166 , 209-219).
  • exposure of corneal fibroblasts to the exogenous CD147 extracellular domain induces myofibroblast differentiation and MMP production (Huet, E. et al., FASEB J 2008 , 22 , 1144-1154).
  • endogenous CD147 located in the membrane of corneal fibroblasts also contributes to fibrosis. Hu et al.
  • CD147 may act as a receptor and ligand for the adjacent CD147. This is referred to as a homophilic interaction such as dimerization (Mauris, J.
  • SP-8356 shows high binding affinity with CD147 and directly inhibits CD147 dimerization (Pahk, K. et al., J Transl Med 2019 , 17 , 274). Therefore, the inhibitory effect of SP-8356 on CD147 dimerization may contribute to the anti-fibrosis effect in alkaline burn corneas.
  • Topical corticosteroids are frequently used to prevent corneal opacity in clinical practice, and PA is one of the popular topical steroids (Wilson, SE, Exp Eye Res 2012 , 99 , 78-88; Baek, SH et al., J Refract Surg). 1997 , 13 , 644-652; Vetrugno, M. et al., Acta Ophthalmol Scand 2001 , 79 , 23-27; Pleyer, U. et al., Ophthalmol Ther 2013 , 2 , 55-72; Hindman, HB et al. ., Exp Eye Res 2019 , 181 , 49-60). Therefore, PA was used as a positive control drug.
  • HA itself has an ameliorating effect to treat corneal epithelial defects and is widely used in dry eye syndrome and corneal epithelial diseases (Rah, MJ, Optometry 2011 , 82 , 38-43; Zhong, J. et al., J Ophthalmol 2016 , 2016 , 6538051; Carlson, E. et al., J Ocul Pharmacol Ther 2018 , 34 , 360-364).
  • the viscoelastic properties of HA extend its stay on the corneal surface (Singh, A. et al., Cont Lens Anterior Eye 2015 , 38 , 79-84). Therefore, SP-8356 was treated with diluted HA to prolong the ocular residence time of SP-8356.
  • SP-8356 after administration of SP-8356 itself or its prodrug SP1154, SP-8356 inhibits CD147 binding and inhibits corneal opacity and related myofibroblast differentiation through MMP-9 activation. In addition, SP-8356 exhibits a superior antifibrotic effect on damaged cornea compared to corticosteroids (PA). Although further studies are needed to elucidate the detailed underlying mechanisms of the antifibrotic effect of SP-8356 in damaged corneas, SP-8356 may be a potential treatment for pathological corneal fibrosis causing corneal opacity.
  • PA corticosteroids
  • the homeostasis of the cornea and conjunctiva depends entirely on the secretion of tears and fatty glands, and if there is a problem with the secretion, it leads to an increase in MMP in the cornea and conjunctiva.
  • MMP9 directly causes damage to the extracellular matrix in the cornea and conjunctival epithelium depending on the concentration in the tear, leading to inflammatory cell infiltration and increased corneal thickness.
  • Corneal surface damage is an indicator in the model of dry eye.
  • the drug efficacy was evaluated through fluorescein staining of the ocular surface of the dry eye, and is shown in FIG. 5 .
  • the corneal surface of the eye treated with the drug SP-1154 (BAC+ SP-1154 OD, right) compared with the left eye induced by BAC treatment with fluorescence It was confirmed that the damaged corneal epithelium was significantly reduced.
  • SP-8356 had the ability to inhibit corneal surface damage in the dry eye model like restasis. Since damage to the corneal surface leads to subsequent angiogenesis or infiltration of inflammatory cells, suppressing it is a major indicator of the evaluation of a treatment for dry eye.
  • Restasis is a commercially available dry eye treatment containing 1% Cyclosporin as a main ingredient and is used as a comparative drug, and BAC (benzalkonium chloride) is a dry eye inducing drug.
  • F4/80 and CD31 expression decreased in the cornea and conjunctiva when the prodrug SP-1154 was treated ( FIG. 6 , CD31: vascular endothelial cell, F4/80: macrophage, inflammation marker).
  • CD31 vascular endothelial cell
  • F4/80 macrophage, inflammation marker.
  • SP-8356 blocked the infiltration of inflammatory cells at a level similar to that of restasis, but its ability to inhibit angiogenesis was judged to be inferior to that of restasis.
  • CD11b inflammatory macrophage infiltration marker
  • SP-8356 inhibited macrophage infiltration and MMP9 expression similar to or more than restasis in an animal model of dry eye.
  • Table 1 summarizes the effects of berbenone derivatives on dry eye syndrome.
  • the compound of Formula 1 according to the present invention can prevent corneal opacity by preventing pathologic fibrosis after severe corneal damage, and thus can be a potentially promising therapeutic agent for corneal fibrosis.
  • the pharmaceutical composition comprising the berbenone derivative according to the present invention as an active ingredient inhibits CD147 binding, inhibits corneal opacity and related myofibroblast differentiation through MMP-9 activation, and is damaged compared to the existing drug, corticosteroid (PA). It shows an excellent anti-fibrotic effect on the cornea. Therefore, it is possible to treat and prevent eye diseases by suppressing eye damage and inflammation, such as conjunctivitis, corneal burns, or dry eye syndrome, and alleviating symptoms.

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Abstract

La présente invention se rapporte à une composition pharmaceutique ou à un aliment fonctionnel de santé destiné au traitement ou à la prévention de maladies oculaires, comprenant un dérivé de verbénone et un sel pharmaceutiquement acceptable de cette dernière en tant que principes actifs. Plus précisément, le dérivé de verbénone de la présente invention agit en tant qu'inhibiteur de CD147 qui affaiblit la fibrose cornéenne et inhibe l'opacité cornéenne et la différenciation en myofibroblastes associée par l'activation de MMP-9, et peut ainsi traiter et prévenir des maladies oculaires en supprimant des lésions oculaires et l'inflammation, telles que la conjonctivite, la brûlure de la cornée ou le syndrome de l'œil sec, et en soulageant les symptômes.
PCT/KR2021/005067 2020-04-22 2021-04-22 Composition pharmaceutique destinée au traitement ou à la prévention de maladies oculaires comprenant un dérivé de verbénone WO2021215836A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000063159A1 (fr) * 1999-04-16 2000-10-26 Euphar Group Srl Derives de (-)-verbenone
JP2007530538A (ja) * 2004-03-25 2007-11-01 セントカー・インコーポレーテツド 過剰血管新生と関連する疾患の処置のためのｅｍｍｐｒｉｎアンタゴニストの使用
KR20200029772A (ko) * 2018-09-11 2020-03-19 고려대학교 산학협력단 베르베논 유도체를 포함하는 암 치료 또는 예방용 조성물

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000063159A1 (fr) * 1999-04-16 2000-10-26 Euphar Group Srl Derives de (-)-verbenone
JP2007530538A (ja) * 2004-03-25 2007-11-01 セントカー・インコーポレーテツド 過剰血管新生と関連する疾患の処置のためのｅｍｍｐｒｉｎアンタゴニストの使用
KR20200029772A (ko) * 2018-09-11 2020-03-19 고려대학교 산학협력단 베르베논 유도체를 포함하는 암 치료 또는 예방용 조성물

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Title
ERIC HUET, ET AL: "EMMPRIN Modulates Epithelial Barrier Function through a MMP–Mediated Occludin Cleavage", THE AMERICAN JOURNAL OF PATHOLOGY, ELSEVIER INC., US, vol. 179, no. 3, 1 September 2011 (2011-09-01), US , pages 1278 - 1286, XP055380013, ISSN: 0002-9440, DOI: 10.1016/j.ajpath.2011.05.036 *
GABISON, E.E. ; HUET, E. ; BAUDOUIN, C. ; MENASHI, S.: "Direct epithelial-stromal interaction in corneal wound healing: Role of EMMPRIN/CD147 in MMPs induction and beyond", PROGRESS IN RETINAL AND EYE RESEARCH, OXFORD, GB, vol. 28, no. 1, 1 January 2009 (2009-01-01), GB , pages 19 - 33, XP025947154, ISSN: 1350-9462, DOI: 10.1016/j.preteyeres.2008.11.001 *
PAHK KISOO, NOH HYOJIN, JOUNG CHANMIN, JANG MI, SONG HWA YOUNG, KIM KYUNG WON, HAN KIHOON, HWANG JONG-IK, KIM SUNGEUN, KIM WON-KI: "A novel CD147 inhibitor, SP-8356, reduces neointimal hyperplasia and arterial stiffness in a rat model of partial carotid artery ligation", JOURNAL OF TRANSLATIONAL MEDICINE, vol. 17, no. 1, 1 December 2019 (2019-12-01), XP055859550, DOI: 10.1186/s12967-019-2024-y *

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