WO2023274817A1 - Dérivés de 1-hydroxy-pyridin-2-one destinés à être utilisés dans le traitement des cicatrices - Google Patents

Dérivés de 1-hydroxy-pyridin-2-one destinés à être utilisés dans le traitement des cicatrices Download PDF

Info

Publication number
WO2023274817A1
WO2023274817A1 PCT/EP2022/067071 EP2022067071W WO2023274817A1 WO 2023274817 A1 WO2023274817 A1 WO 2023274817A1 EP 2022067071 W EP2022067071 W EP 2022067071W WO 2023274817 A1 WO2023274817 A1 WO 2023274817A1
Authority
WO
WIPO (PCT)
Prior art keywords
therapeutic compound
hydroxy
substituted
cutaneous
scar
Prior art date
Application number
PCT/EP2022/067071
Other languages
English (en)
Inventor
Selim Cellek
Alice LAPTHORN
Marcus Ilg
Peter DZIEWULSKI
Original Assignee
Anglia Ruskin University Higher Education Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Anglia Ruskin University Higher Education Corporation filed Critical Anglia Ruskin University Higher Education Corporation
Publication of WO2023274817A1 publication Critical patent/WO2023274817A1/fr

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like

Definitions

  • the present invention relates to the treatment of scarring, in particular the prevention of the formation of cutaneous scars or the reduction of their severity.
  • Cutaneous scarring following severe injury remains a significant issue, which can lead to psychosocial and physical problems such as contractures, itch, pain and disfigurement.
  • severe injury e.g. burns
  • the management of cutaneous scars is one of the greatest unmet challenges in the treatment of bum injuries.
  • Post-burn scars usually manifest as hypertrophic or keloid lesions, with severe cases of hypertrophic scarring manifesting as contractures.
  • the current treatment strategy for cutaneous scarring involves surgical excision of the scars, with patients encouraged to massage the affected area. There are no approved medications for the prevention of cutaneous scarring (1-3).
  • fibrosis which is the excessive accumulation of extracellular matrix (ECM) proteins in the affected tissue. Fibrosis is a result of aberrant wound healing, where the physiological control mechanisms that limit wound healing are lost.
  • ECM extracellular matrix
  • resident skin fibroblasts are activated by local inflammation, secondary to physical or chemical injury to the tissue. Activated fibroblasts transform into myofibroblasts which have high proliferative capacity, ability to produce high amounts of ECM and are able to contract. Once the wound is healed, the myofibroblasts are expected to go through apoptosis and be removed from the wound site by phagocytes.
  • the present inventors have identified a class of compounds (substituted 1-hydroxy-pyridin-2-ones) that inhibit the transformation of dermal fibroblasts into myofibroblasts and may therefore be useful in preventing, reducing or inhibiting the formation of cutaneous scars following injury.
  • a first aspect of the invention provides a method of preventing, or inhibiting the formation of a cutaneous scar or reducing the severity of a cutaneous scar comprising; administering a therapeutic compound to an individual in need thereof, wherein the therapeutic compound is a substituted 1 -hydroxy-pyridin-2-one, such as a 6-substituted 1-hydroxy-4-methylpyridin-2-one, or a salt or solvate thereof.
  • a second aspect of the invention provides a method of suppressing cutaneous fibrosis in an individual in need thereof comprising; administering a therapeutic compound to the individual, wherein the therapeutic compound is a substituted 1 -hydroxy-pyridin-2-one, such as a 6-substituted
  • a third aspect of the invention provides a method of inhibiting the transformation of fibroblasts to myofibroblasts in a cutaneous wound comprising; administering a therapeutic compound to an individual in need thereof, wherein the therapeutic compound is a substituted 1 -hydroxy-pyridin-2-one, such as a 6-substituted
  • a fourth aspect of the invention provides a therapeutic compound for use in a method of any one of the first to the third aspects, wherein the therapeutic compound is a substituted 1 -hydroxy-pyridin-2-one, such as a 6-substituted
  • a fifth aspect of the invention provides the use of a therapeutic compound in the manufacture of a medicament for use in a method any one of the first to the third aspects, wherein the therapeutic compound is a substituted 1-hydroxy-pyridin-2-one, such as a 6-substituted 1-hydroxy-4-methylpyridin-2-one, or a salt, or solvate thereof.
  • the therapeutic compound is ciclopirox, ciclopirox olamine (ciclopirox ethanolamine), piroctone olamine (piroctone ethanolamine; octopiroxTM) or rilopirox.
  • the therapeutic compound is formulated in a topical pharmaceutical composition.
  • Figure 1 shows the effect of ciclopirox (CPX; circles), ciclopirox ethanolamine (CPXO; squares) and octopiroxTM (OPX; triangles) on TGF-bI -induced transformation of human primary skin fibroblasts to myofibroblasts as measured with a-SMA expression using in-cell ELISA (ICE).
  • CPX ciclopirox
  • CPXO ciclopirox ethanolamine
  • OPX octopiroxTM
  • Figure 2 shows the effect of ciclopirox (CPX; circles), ciclopirox ethanolamine (CPXO; squares) and octopiroxTM (OPX; triangles) on TGF-bI -induced epithelial-mesenchymal transition of human keratinocytes as measured with vimentin expression using ICE.
  • CPX ciclopirox
  • CPXO ciclopirox ethanolamine
  • OPX octopiroxTM
  • Figure 3 shows the effect of ciclopirox (CPX; circles), ciclopirox ethanolamine (CPXO; squares) and octopiroxTM (OPX; triangles) on TGF-bI -induced epithelial-mesenchymal transition of human keratinocytes as measured with fibronectin expression using ICE.
  • Figure 4 shows the effect of ciclopirox (CPX; circles), ciclopirox ethanolamine (CPXO; squares) and octopiroxTM (OPX; triangles) on TGF-bI -induced extracellular matrix (ECM) protein production in human primary fibroblasts as measured using Coomassie blue staining.
  • CCM extracellular matrix
  • Figure 5 shows the effect of ciclopirox (CPX) on cell viability of pre-transfomned myofibroblasts (squares) or TGF ⁇ 1-induced transformation of fibroblasts to myofibroblasts (circles) as measured using DRAQ5 nuclear staining.
  • CPX ciclopirox
  • Figure 6 shows the effect of ciclopirox ethanolamine (CPXO) on cell viability of pre-transformed myofibroblasts (squares) or TGF-bI -induced transformation of fibroblasts to myofibroblasts (circles) as measured using DRAQ5 nuclear staining.
  • CPXO ciclopirox ethanolamine
  • Figure 7 shows the effect of octopiroxTM (OPX) on cell viability of pre-transformed myofibroblasts (squares) or TGF-bI -induced transformation of fibroblasts to myofibroblasts (circles) as measured using DRAQ5 nuclear staining.
  • OPX octopiroxTM
  • the methods described herein relate to the prevention or inhibition of cutaneous scarring and/or the reduction of severity of cutaneous scarring through the administration of a therapeutic compound described herein.
  • the therapeutic compound may be for example topically administered to the site of a cutaneous wound or injury. Inhibition of one or more of the transformation of fibroblasts to myofibroblasts; the keratinocyte epithelial-mesenchymal transition and total ECM production in the cutaneous wound or injury by the therapeutic compound may suppress fibrosis and prevent or inhibit the formation of a cutaneous scar or reduce severity of a cutaneous scar.
  • a suitable therapeutic compound for use as described herein may be a substituted 1-hydroxy-pyridin-2-one, such as a 6-substituted 1-hydroxy-4-methylpyridin-2-one, or a salt or solvate thereof.
  • Substituted 1-hydroxy-pyridin-2-ones are well known in the art, and their preparation is well documented. Such compounds, and preferably those 1 -hydroxy-pyridin-2-one compounds of formula (I) and (II) described below, may be used in the methods of the invention.
  • the substituted 1-hydroxy-pyridin-2-one may be substituted at the 4-position of the pyridine-2-one, and it may be substituted at the 6-position of the pyridine-2-one.
  • the 1 -hydroxy-pyridin-2-one is disubstituted at the 4- and 6-positions.
  • the substituents are not limited, and may include alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl, and these groups may be optionally substituted.
  • the substituted 1-hydroxy-pyridin-2-one may have the formula (I). where -R 6 is independently selected from alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aralkenyl, and aralkoxy;
  • -R 4 is independently selected from hydrogen, alkyl, cycloalkyl, aryl, aralkyl, nitro, cyano and halogen; or a salt or solvate thereof.
  • the pyridine-2-one is substituted at the 4-position.
  • -R 4 is not hydrogen.
  • An alkyl group may be linear or branched.
  • the alkyl group may be C1-12 alkyl, such as C1-10 alkyl, such as C1-6 alkyl, and such as C alkyl.
  • an alkyl group may be C4-12, such as C4-10, such as C6-10 alkyl.
  • Such larger alkyl groups are preferred at -R 6 .
  • An alkenyl group may contain one or more carbon-carbon double bonds, where appropriate, and preferably one double bond only.
  • An alkenyl group may be linear or branched.
  • the alkenyl group may be C2-12 alkenyl, such as C2-10 alkenyl, such as C2-6 alkenyl, and such as C2-4 alkenyl.
  • a cycloalkyl group may be C3-12 cycloalkyl.
  • the cycloalkyl group may have one ring or two fused rings, and preferably one ring.
  • the cycloalkyl group may be Ce-10 alkyl, and is preferably C6 cyclohexyl (cyclohexyl).
  • An aryl group may be a carboaryl or a heteroaryl.
  • the aryl group may have one ring or two fused rings, where the fused ring system is aromatic.
  • a carboaryl group may be Ce-io carboaryl, such as phenyl or naphthyl.
  • a heteroaryl group be C5-10 heteroaryl such as C5-6 heteroaryl, such as C5 or Ce heteroaryl.
  • Examples of Cs heteroaryl include pyrrolyl, pyrazolyl, thiphenyl, oxazoyl and furanyl, amongst others.
  • Examples of Oe heteroaryl include pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl.
  • An aralkyl group is an aryl group connected via an alkylene linker.
  • the aryl group may be an aryl group as described above.
  • An alkylene group may be linear or branched.
  • the alkylene group may be C alkyl, such as C alkylene, such as C alkylene, and such as CM alkylene.
  • the alkylene is methylene (-CH -).
  • An example aralkyl group is benzyl.
  • An aralkenyl group is an aryl group connected via an alkenylene linker.
  • the aryl group may be an aryl group as described above.
  • An alkenylene group may contain one or more carbon-carbon double bonds, where appropriate, and preferably one double bond only.
  • An alkenylene group may be linear or branched.
  • the alkenylene group may be C2-12 alkenylene, such as C2-10 alkenylene, such as C2-6 alkenylene, and such as C2-4 alkenylene.
  • An aralkoxy group is an aryl group connected via an alkoxyene linker.
  • the aryl group may be an aryl group as described above.
  • An alkoxyene group is an alkylene group where one or more, such as one, of the carbon atoms is replaced with oxygen, and the alkoxyene group contains at least one carbon atom.
  • the alkoxyene group may be C2-12 alkoxyene, such as C2-10 alkoxyene, such as C2-6 alkoxyene, and such as C2-4 alkoxyene.
  • a nitro group is -NO2.
  • a cyano group is -CN.
  • a halogen may be selcted from fluoro, chloro, bromo and iodo, such as from fluoro and chloro.
  • Any alkyl, alkenyl, cycloalkyl, aryl, aralkyl, aralkenyl, or aralkoxy group may be optionally substituted, such as subituted with one or two substituents.
  • Each optional substituent may be independently selected from halogen, cyano, nitro, cycloalkyl and alkyl. These groups may be as described above.
  • a cycloalkyl, aryl, aralkyl, aralkenyl, or aralkoxy group may also be optionally subsitued with alkyl or alkenyl, such as an alkyl or alkenyl group described above.
  • alkyl or alkenyl such as an alkyl or alkenyl group described above.
  • -R 4 is alkyl.
  • the compound may be referred to as a 6-substituted 1-hydroxy-4- alkylpyridin-2-one.
  • -R 4 is selected from methyl and ethyl, and most preferably -R 4 is methyl.
  • -R 6 is independently alkyl or cycloalkyl.
  • -R 6 is an alkyl group
  • this is a branched alkyl group.
  • -R 4 is 2,4,4-trimethylpentyl.
  • -R 6 is a cycloalkyl group, this is cyclohexyl.
  • a 6-substituted 1-hydroxy-4-methylpyridin-2-one may have the formula (II). where -R 6 is selected from alkyl and cycloalkyl, as described above, or a salt or solvate thereof.
  • -R 6 is cyclohexyl; 2,4,4-trimethylpentyl; or4-(4- chlorophenoxy)phenoxy]methyl
  • the 6-substituted 1-hydroxy-4-methylpyridin-2-one is ciclopirox.
  • Ciclopirox (CAS No: 29342-05-0; Pubchem CID: 2749; 6-cyclohexyl-1-hydroxy-4-methylpyridin-2-one) is a synthetic, antifungal agent that binds to and chelates trivalent cations.
  • Ciclopirox is widely available from commercial suppliers or may be synthesised using standard techniques.
  • the 6-substituted 1-hydroxy-4-methylpyridin-2-one is piroctone.
  • Piroctone (CAS No: 50650-76-5; Pubchem CID: 50259; 6-(2,4,4-trimethylpentyl)-1-hydroxy-4-methylpyridin-2-one) is a synthetic antifungal and antidandruff agent Piroctone is widely available from commercial suppliers or may be synthesised using standard techniques.
  • the 6-substituted 1-hydroxy-4-methylpyridin-2-one is rilopirox.
  • Rilopirox (CAS No: 104153-37-9; Pubchem CID: 71778; 6-[[4-(4-chlorophenoxy)phenoxy]methyl]-1-hydroxy-4- methylpyridin-2-one) is a synthetic antifungal agent Rilopirox is widely available from commercial suppliers or may be synthesised using standard techniques.
  • Analogues of ciclopirox, rilopirox and piroctone such as analogues within the scope of formula (I) and (II) are known in the art, and these compounds may be prepared by standard methods of chemical synthesis. Suitable compounds for use in the methods of the present case include those compounds described in, for example, EP 1051203.
  • the therapeutic compound may be provided as a solvate, such as a hydrate, of a substituted 1-hydroxy- pyridin-2-one, such as a 6-substituted 1-hydroxy-4-methylpyridin-2-one.
  • the therapeutic compound may be provided in salt form.
  • the salt may be selected from an organic base, such as an organic amine base, an alkali metal ion, an ammonium ion, an alkaline metal ion, or a divalent, trivalent, or tetravalent cationic ion.
  • Suitable salt forms of a substituted 1-hydroxy-pyridin-2-one may include the ethanolamine salt.
  • suitable therapeutic compounds include piroctone olamine (piroctone ethanolamine; octopiroxTM) and ciclopirox olamine (ciclopirox ethanolamine).
  • a therapeutic compound for example a 6-substituted 1-hydroxy-4-methyl-2(1 H)- pyridinone, such as ciclopirox or piroctone, or an olamine salt thereof, to be administered to the individual alone, it is preferable to present the compound in a pharmaceutical composition or formulation.
  • a pharmaceutical composition may comprise, in addition to the therapeutic compound, one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well-known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active therapeutic compound.
  • the precise nature of the carrier or other material will depend on the route of administration, which may be by bolus, infusion, injection or any other suitable route, as discussed below. Suitable materials will be sterile and pyrogen free, with a suitable isotonicity and stability. Examples include sterile saline (e.g. 0.9% NaCI), water, dextrose, glycerol, ethanol or the like or combinations thereof.
  • the composition may further contain auxiliary substances such as wetting agents, emulsifying agents, pH buffering agents or the like.
  • Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington’s Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well-known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary, shaping the product.
  • Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, lozenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.
  • the therapeutic compound or pharmaceutical compositions comprising the therapeutic compound may be administered to a subject by any convenient route of administration.
  • the therapeutic compound is administered topically, for example to a wound or site of injury on the skin of an individual.
  • a suitable pharmaceutical composition is preferably a topical pharmaceutical composition.
  • a pharmaceutical composition for topical administration may be in the form of, for example, an aqueous or nonaqueous gel, cream, multiple emulsion, microemulsion, liposome, ointment, aqueous or nonaqueous solution, lotion, aerosol, skin patch, wound dressing, plaster, bandage, hydrocarbon base or powder.
  • a pharmaceutical composition may contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols, and amino acids), and hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone).
  • solubilizers e.g., fatty acids, fatty acid esters, fatty alcohols, and amino acids
  • hydrophilic polymers e.g., polycarbophil and polyvinylpyrolidone
  • a pharmaceutical composition for topical administration may be prepared by mixing a therapeutic compound described herein with a topical carrier according to well-known methods in the art, for example, methods provided by standard reference texts e.g., Remington: The Science and Practice of Pharmacy, 1577-1591 , 1672-1673, 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995); and Ghosh et al., Transdermal and Topical Drug Delivery Systems (1997).
  • moisturizers or humectants such as paraffin, jojoba, PABA, and waxes, surfactants, occlusives, hygroscopic agents, emulsifiers, emollients, lipid-free cleansers, antioxidants and lipophilic agents, may be added to the topical pharmaceutical composition, if desired.
  • a pharmaceutical composition for topical administration may be designed to be left on the skin and not washed shortly after application. Alternatively, the pharmaceutical composition may be designed to be rinsed off within a given amount of time after application.
  • T reatment may be any treatment or therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved.
  • a human or an animal e.g. in veterinary applications
  • some desired therapeutic effect is achieved.
  • the onset or progress of cutaneous seaming or fibrosis may be prevented, delayed or inhibited; the rate of progress of the cutaneous scarring or fibrosis may be reduced or halted; the cutaneous scarring or fibrosis may be ameliorated; or one or more symptoms and/or signs of the cutaneous scarring or fibrosis may be prevented, delayed, abated or arrested.
  • a therapeutic compound may be administered as described herein in a therapeutically effective amount.
  • terapéuticaally-effective amount refers to that amount of an therapeutic compound, or a combination, material, composition or dosage form comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.
  • the appropriate dosage of a therapeutic compound may vary from individual to individual. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the administration.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the route of administration, the time of administration, the rate of excretion of the active compound, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the individual.
  • the amount of active compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve therapeutic plasma concentrations of the active compound without causing substantial harmful or deleterious side-effects.
  • a suitable dose of the active compound is in the range of about 100 pg to about 400 mg per kilogram body weight of the subject per day, preferably 200 pg to about 200 mg per kilogram body weight of the subject per day.
  • the active compound is a salt, an ester, prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • a therapeutic compound described herein may be topically administered in an amount sufficient to maintain a concentration at a level that yields >50% inhibition of transformation of dermal fibroblasts into myofibroblasts; >50 inhibition of keratinocyte epithelial-mesenchymal transition and/or >50 inhibition of ECM production by myofibroblasts.
  • a therapeutic compound described herein may be topically administered in an amount sufficient to maintain a tissue concentration of 1 pM or more, 5 pM or more, 10 pM or more or 15 pM or more.
  • a pharmaceutical composition for topical administration may for example comprise 0.1 % to 10% active compound, for example 0.5% to 8% active compound.
  • Administration of a therapeutic compound in vivo many be affected in one dose, continuously or intermittently (e.g., in divided doses at appropriate intervals).
  • Methods of determining the most effective means and dosage of administration are well known in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the physician.
  • Multiple doses of the therapeutic compound may be administered, for example 2, 3, 4, 5 or more than 5 doses may be administered.
  • the administration of the therapeutic compound may continue for sustained periods of time.
  • treatment with the therapeutic compound may be continued for at least 1 week, at least 2 weeks, at least 3 weeks, at least 1 month or at least 2 months.
  • T reatment with a therapeutic compound described herein may be continued for as long as is necessary to reduce symptoms or prevent cutaneous scarring or fibrosis.
  • a therapeutic compound described herein may be administered alone or in combination with other treatments, either simultaneously or sequentially dependent upon the individual circumstances.
  • a therapeutic compound described herein may be administered in combination with one or more additional active compounds.
  • the therapeutic compounds described herein are shown herein to be useful in inhibiting the transformation of dermal fibroblasts into myofibroblasts.
  • the therapeutic compounds described herein are also shown herein to be useful in inhibiting keratinocyte epithelial-mesenchymal transition and total ECM production.
  • the therapeutic compounds described herein are also shown herein to be useful in inducing apoptosis in pretransformed myofibroblasts.
  • the therapeutic compounds described herein may thus be useful in suppressing fibrosis in a cutaneous wound and find therapeutic application in preventing, or inhibiting the formation of a cutaneous scar and/or reducing the severity of a cutaneous scar.
  • the transformation of dermal fibroblasts into myofibroblasts may be determined using any convenient technique. Suitable techniques are described herein.
  • the TGF-bI -induced expression of a myofibroblast marker such as a-SMA (alpha smooth muscle actin) may be determined in human primary skin fibroblasts.
  • Keratinocyte epithelial-mesenchymal transition may be determined using any convenient technique. Suitable techniques are described herein. In some embodiments, the TGF-bI -induced expression of vimentin and fibronectin may be determined in human keratinocytes.
  • ECM production by myofibroblasts may be determined using any convenient technique. Suitable techniques are described herein. In some embodiments, the TGF-bI -induced production of extracellular matrix protein in human primary skin cells may be determined.
  • Cell viability of dermal fibroblast and myofibroblasts may be determined using any convenient technique. Suitable techniques are described herein. In some embodiments, cell viability may be determined by staining nuclear proteins in dermal fibroblasts and myofibroblasts using DRAQ5.
  • a cutaneous scar is a scar that forms at a wound or site of injury in the dermal or cutaneous tissue of an individual.
  • a cutaneous scar may be associated with aberrant wound healing.
  • a cutaneous scar as described herein may be an excessive, aberrant or pathological cutaneous scar, for example a hypertrophic scar, keloid or scar contracture.
  • a method described herein may be useful in preventing, reducing or inhibition the formation of an excessive, aberrant or pathological cutaneous scar.
  • a cutaneous scar may form after an injury or wound affecting dermal or cutaneous tissue, such as a burn.
  • An individual suitable for treatment as described herein may have a wound or injury that is at risk of or in the process of developing a cutaneous scar.
  • the therapeutic compound may be administered to a cutaneous wound or site of cutaneous injury, for example a bum injury.
  • the therapeutic compound may be administered to the individual following initial infection control and debridement.
  • the compound may be administered at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days or at least 18 days after the occurrence of the injury.
  • An individual suitable for treatment as described above may be a mammal, such as a rodent (e.g. a guinea pig, a hamster, a rat), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), leporine (e.g. a rabbit), porcine (e.g. a pig), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orang-utan, gibbon), or a human.
  • a rodent e.g. a guinea pig, a hamster, a rat
  • murine e.g. a mouse
  • canine e.g. a dog
  • feline e.g.
  • the individual is a human.
  • non-human mammals especially mammals that are conventionally used as models for demonstrating therapeutic efficacy in humans (e.g. murine, primate, porcine, canine, or leporid) may be employed.
  • fibroblast growth was monitored using a light microscope (Nikon Instruments Europe, UK) and if fibroblast outgrowth was observed, the tissue was removed from the wells. All explant tissue was placed into cryotubes (Nunc Fisher Scientific, UK) and stored at -80°C. The cells were washed twice with warm PBS, before being given fresh 20% FCS media and incubated at 37°C, 5% C02. Once the cells had reached 70-90% confluency, old media was removed, and the cells washed twice with warm PBS. Cells were detached using 500 pi of 0.25% trypsin/0.03% EDTA (Gibco Invitrogen, UK), which was neutralised with 1 mL 20% FCS media. The cell suspension was transferred to a T75 flask (Nunc Fisher Scientific, UK), containing 11 mL of 20% FCS media, and incubated at 37°C, 5% C02.
  • the old media was removed, and the cells washed with warm PBS.
  • the media was switched to media consisting of DMEM-F12, 10% FCS, 1% Pen/Strep and 4 ng/mL of human basic fibroblast growth factor (hBFGF; Sigma-Aldrich, UK) - this media will hereby be referred to as complete media.
  • hBFGF human basic fibroblast growth factor
  • the plates were washed three times for 5 min using 0.1 % Triton X-100 in PBS, before a blocking solution of 10% donkey serum in 0.1% Triton X-100 in PBS was added. The plates were incubated for 90 min at room temperature on an orbital shaker.
  • the blocking solution was then removed from the wells and replaced with anti-a-SMA antibody raised in mouse (Sigma-Aldrich, UK - cat #A5228; 1 :3,000 in PBS), anti-vimentin antibody raised in mouse (Abeam, UK - cat #ab8069; 1 :3,000 in PBS) or anti-fibronectin antibody raised in mouse (eBioscience, UK - cat# 15228197; 1 :1 ,000 in PBS).
  • the plates were incubated at room temperature on an orbital shaker for 2 h. The cells were washed three times with 0.1% Tween 20 in PBS, with each wash lasting for 5 min.
  • the secondary antibody 800 nm IRdye donkey anti-mouse/anti-rabbit, 1:500 dilution; Li-Cor, UK
  • nuclear stain DRAQ5, 1:1000 dilution; Biostatus, UK
  • the plates were washed three times with 0.1% Tween 20 in PBS, then once with blank PBS. All liquid was removed from the wells before scanning.
  • the plates were scanned using a near-infrared scanner (Odyssey CLx imager; Li-Cor, UK), in the 700 nm and 800 nm channels.
  • the primary fibroblasts were seeded at a density of 4,000 cells per well into black optical 96-well plates and left to adhere overnight at 37°C and 5% C02. The following day, the old media was removed and replaced with either fresh blank media or media containing the desired TGF-bI and/or drug concentrations. The plates were incubated for 7 days at 37°C and 5% C02. Following the incubation period, the old media was removed from each well carefully (to prevent disruption of the ECM) and replaced with 100 pi of DRAQ5 diluted in PBS at a dilution of 1 :1000.
  • the plates were incubated at 37°C and 5% C02 for 5 min, before removing the DRAQ5 solution and scanning the plate using the Odyssey CLx imager in the 700 nm channel.
  • 100 pi of 0.25 M ammonium hydroxide in water was added to each well and incubated at 37°C and 5% C02 for 10 min.
  • the ammonium hydroxide was removed from the wells and the plates were washed using PBS.
  • the ECM was fixed using a solution of 50% methanol and 7.5% acetic acid in distilled water.
  • 100 mI of the fixing solution was added to each well, and incubated for 1 h at -20°C. The fixing solution was removed carefully and each well washed with cold PBS.
  • the ECM was stained using Coomassie blue (Fisher Scientific, UK) to measure total ECM production. 100 mI of Coomassie Blue (0.05% w/v) was added to each well and the plates incubated for 72 h at 4°C. Following incubation with Coomassie blue, the stain was removed, and the wells were washed carefully using 100 mI cold PBS. The plates were scanned using the Odyssey CLx imager in the 700 nm channel. For data analysis, the Coomassie measurements were normalized to the cell number obtained previously.
  • Ciclopirox (CPX), ciclopirox ethanolamine (CPXO) and octopiroxTM (OPX) were found to inhibit TGF-bI- induced transformation of human primary fibroblasts in a concentration-dependent manner; measured as a- SMA expression using ICE ( Figure 1).
  • Ciclopirox (CPX), ciclopirox ethanolamine (CPXO) and octopiroxTM (OPX) were then found to inhibit TGF-bI- induced epithelial-mesenchymal transition (EMT) of keratinocytes in a concentration-dependent manner; measured as vimentin expression using ICE ( Figure 2).
  • EMT TGF-bI- induced epithelial-mesenchymal transition
  • Figure 2 The IC50 values for CPX, CPXO and OPX were calculated as 17.7 ⁇ 3.2 pM, 21 .8 ⁇ 6.9 pM and 9.5 ⁇ 4.1 pM respectively.
  • Ciclopirox (CPX), ciclopirox ethanolamine (CPXO) and octopiroxTM (OPX) inhibit TGF-bI -induced epithelial- mesenchymal transition (EMT) of keratinocytes in a concentration-dependent manner; measured as fibronectin expression using ICE ( Figure 3).
  • EMT TGF-bI -induced epithelial- mesenchymal transition
  • Figure 3 The IC50 values for CPX, CPXO and OPX were calculated as 1.5 ⁇ 0.2 pM, 14.4 ⁇ 2.6 pM and 11.1 ⁇ 1.6 pM respectively.
  • Ciclopirox (CPX), ciclopirox ethanolamine (CPXO) and octopiroxTM (OPX) inhibit TGF-bI -induced extracellular matrix (ECM) protein production in human primary fibroblasts in a concentration-dependent manner; measured as Coomassie blue staining ( Figure 4).
  • the ICso values for CPX, CPXO and OPX were calculated as 20.9 ⁇ 2.5 pM, 19.9 ⁇ 6.3 pM and 5.2 ⁇ 3.5 pM respectively.
  • hydroxypyridones were identified as hits in a phenotypic screening assay where the transformation of human primary skin fibroblasts to myofibroblasts are measured. All three hydroxypyridones inhibited (i) TGF-bI -induced a-SMA expression in human primary skin fibroblasts in a concentration dependent manner (ii) TGF-bI -induced vimentin and fibronectin expression in human keratinocytes in a concentration dependent manner and (iii) TGF ⁇ 1-induced extracellular matrix protein production in human primary skin fibroblasts in a concentration dependent manner.
  • concentrations that are required to show anti-fibrotic effects of the three drugs are within the range of concentrations that these drugs can reach in human skin when applied topically. These concentrations have also been shown to be safe (8, 9).
  • hydroxypyridones such as ciclopirox, ciclopirox ethanolamine and octopiroxTM
  • CPX ciclopirox
  • CPXO ciclopirox ethanolamine
  • OPX piroctone olamine

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de traitement des cicatrices, en particulier la prévention de la formation de cicatrices cutanées ou la réduction de leur gravité par l'administration d'un composé 1-hydroxy-pyridine-2-one substitué, tel qu'un 1-hydroxy-4-méthylpyridine-2-one 6-substitué, ou un sel ou un solvate de celui-ci à un individu en ayant besoin. Les composés de 1-hydroxy-pyridine-2-one substitués appropriés comprennent le ciclopirox, le ciclopirox olamine, la piroctone olamine et le rilopirox.
PCT/EP2022/067071 2021-07-01 2022-06-22 Dérivés de 1-hydroxy-pyridin-2-one destinés à être utilisés dans le traitement des cicatrices WO2023274817A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB2109534.4A GB202109534D0 (en) 2021-07-01 2021-07-01 Treatment of scarring
GB2109534.4 2021-07-01

Publications (1)

Publication Number Publication Date
WO2023274817A1 true WO2023274817A1 (fr) 2023-01-05

Family

ID=77274504

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2022/067071 WO2023274817A1 (fr) 2021-07-01 2022-06-22 Dérivés de 1-hydroxy-pyridin-2-one destinés à être utilisés dans le traitement des cicatrices

Country Status (2)

Country Link
GB (1) GB202109534D0 (fr)
WO (1) WO2023274817A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1051203A1 (fr) 1998-01-28 2000-11-15 The Procter & Gamble Company Absorbants polymeres formant un hydrogel et antimicrobiens
WO2015120350A2 (fr) * 2014-02-07 2015-08-13 Effector Therapeutics, Inc. Compositions et méthodes pour traiter des maladies fibrosantes
WO2020172113A1 (fr) * 2019-02-18 2020-08-27 Lankenau Institute For Medical Research Matériaux de fermeture de plaie réduisant la cicatrice
US20200352918A1 (en) * 2019-05-07 2020-11-12 Brigitte N. Gomperts Compounds and methods for treating or preventing fibrosis

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1051203A1 (fr) 1998-01-28 2000-11-15 The Procter & Gamble Company Absorbants polymeres formant un hydrogel et antimicrobiens
WO2015120350A2 (fr) * 2014-02-07 2015-08-13 Effector Therapeutics, Inc. Compositions et méthodes pour traiter des maladies fibrosantes
WO2020172113A1 (fr) * 2019-02-18 2020-08-27 Lankenau Institute For Medical Research Matériaux de fermeture de plaie réduisant la cicatrice
US20200352918A1 (en) * 2019-05-07 2020-11-12 Brigitte N. Gomperts Compounds and methods for treating or preventing fibrosis

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"Remington: The Science and Practice of Pharmacy", vol. 1577-1591, 1995, pages: 866 - 885
"Remington's Pharmaceutical Sciences", 1990, MACK PUBLISHING COMPANY
BAYAT, A.MCGROUTHER, D.A.FERGUSON, M.W.J, SKIN SCARRING. BRITISH MEDICAL JOURNAL, vol. 326, no. 7380, 2003, pages 88 - 92
BOLLONG, M.J.YANG, B.VERGANI, N.BEYER, B.A.CHIN, E.N.ZAMBALDO, C.WANG, D.CHATTERJEE, A.K.LAIRSON, L.L.SCHULTZ, P.G: "Small molecule-mediated inhibition of myofibroblast transdifferentiation for the treatment of fibrosis", PROC NATL ACAD SCI U S A, vol. 114, no. 18, 2017, pages 4679 - 4684, XP055659811, DOI: 10.1073/pnas.1702750114
CESCHIN-ROQUES, C.G.HANEL, H.PRUJA-BOUGARET, S.MLAGARDE, I.VANDERMANDER, J.MICHEL, G.: "Ciclopirox olamine cream 1%: In vitro and in vivo penetration into the stratum corneum", SKIN PHARMACOLOGY AND PHYSIOLOGY, vol. 4, no. 2, 1991, pages 95 - 99
FINNERTY, C.JESCHKE, M.BRANKSI, L.BARRET, JDZIEWULSKI, P.HERNDON, D.: "Hypertrophic scarring: the greatest unmet challenge following burn injury", THE LANCET, vol. 4, no. 11, 2017, pages 1427 - 1436
GHOSH ET AL., TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS, 1997
JUE, S.GDAWSON, G.W.BROGDEN, R.N.: "Ciclopirox Olamine 1% Cream: A Preliminary Review of its Antimicrobial Activity and Therapeutic Use", DRUGS, vol. 29, no. 4, 1985, pages 330 - 341
LAPTHORN A ET AL: "Hydroxypyridone antifungals display antifibrotic effects in in vitro models of hypertrophic scarring", BRITISH JOURNAL OF DERMATOLOGY, 1 April 2022 (2022-04-01), XP055961379, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/10.1111/bjd.21248> [retrieved on 20220915] *
LAPTHORN ALICE RUTH: "DEVELOPMENT OF A HIGH-THROUGHPUT, PHENOTYPIC SCREENING ASSAY TO IDENTIFY NOVEL MEDICINES TO PREVENT DERMAL SCARRING", THESIS, 1 June 2021 (2021-06-01), XP055955021, Retrieved from the Internet <URL:https://arro.anglia.ac.uk/id/eprint/707450/1/Lapthorn_2021.pdf> [retrieved on 20220825] *
NANTHAKUMAR, C.B.HATLEY, R.J.D.LEMMA, S.GAULDIE, J.MARSHALL, R.P.MACDONALD, S.J.F.: "Dissecting fibrosis: Therapeutic insights from the small-molecule toolbox", NATURE REVIEWS DRUG DISCOVERY, vol. 14, no. 10, 2015, pages 693 - 720
PRAKASH, J.PINZANI, M.: "Fibroblasts and extracellular matrix: Targeting and therapeutic tools in fibrosis and cancer", ADVANCED DRUG DELIVERY REVIEWS, vol. 121, 2017, pages 1 - 2, XP085293229, DOI: 10.1016/j.addr.2017.11.008
WANG ZHIBO ET AL: "Quantitative Immunocytochemistry (QICC)-Based Approach for Antifibrotic Drug Testing in vitro", 13TH INTERNATIONAL CONFERENCE ON BIOMEDICAL ENGINEERING, 1 January 2009 (2009-01-01), XP055955019, Retrieved from the Internet <URL:https://link.springer.com/chapter/10.1007/978-3-540-92841-6_364> [retrieved on 20220825] *
WOLFRAM, D.TZANKOV, A.PULZL, P.PIZA-KATZER, H.: "Hypertrophic scars and keloids - A review of their pathophysiology, risk factors, and therapeutic management", DERMATOLOGIC SURGERY, vol. 35, no. 2, 2009, pages 171 - 181
WYNN, T.RAMALINGAM, T: "Mechanism of fibrosis: therapeutic translation for fibrotic disease", NATURE MEDICINE, vol. 18, no. 7, 2013, pages 1028 - 1040, XP055365554, DOI: 10.1038/nm.2807

Also Published As

Publication number Publication date
GB202109534D0 (en) 2021-08-18

Similar Documents

Publication Publication Date Title
RU2671492C2 (ru) Композиции, содержащие берберин или его аналоги для лечения кожных заболеваний, связанных с розацеа или с покраснением лица
EP1878428A1 (fr) 5-méthyl-2-(1h)-pyridone substituée en 1 par un groupement phényle dans la fabrication de médicaments pour le traitement de la fibrose d&#39;organes ou de tissus
JP4987209B2 (ja) 瘢痕形成作用を有する医薬品を製造するためのビグアニド誘導体の使用
US20240180922A1 (en) Treatments for diabetic neuropathy
KR20180094915A (ko) 건선, 아토피성 피부염, 만성 두드러기, 항히스타민-내성 가려움증 및 노인성 가려움증의 치료를 위한 암보라 추출물 및 녹차 추출물을 포함하는 조성물
US8816065B2 (en) Pharmaceutical or cosmetic composition containing nicotinic acid adenine dinucleotide phosphate or derivative thereof
KR102149851B1 (ko) 염증성 피부 질환 개선을 위한 소듐서팩틴의 신규 용도
KR20080005525A (ko) 습진 치료를 위한 옥사프로진 또는 밀접관련 화합물
EP1804797B1 (fr) Emploi d&#39;un dérivé de pyridine dans la préparation d&#39;un médicament pour le traitement des lésions cutanées
JP2023184678A (ja) 皮膚線維症を処置するための組成物および方法
KR101792402B1 (ko) 니코틴산 아데닌 디뉴클레오티드 인산 및 그 유도체를 포함하는 발모 또는 육모 촉진제
WO2023274817A1 (fr) Dérivés de 1-hydroxy-pyridin-2-one destinés à être utilisés dans le traitement des cicatrices
US20160243080A1 (en) Formulations of angiotensin receptor blockers
JP7453724B2 (ja) ベンズブロマロンを含む傷または瘢痕の予防または治療用薬学組成物
US20220296618A1 (en) Anti-inflammatory compounds for use in the treatment of dermal disorders
CN113521071A (zh) 氯喹那多的新应用
JPH05271226A (ja) 創傷治癒促進剤
KR102691959B1 (ko) 파모인산을 유효성분으로 포함하는 가려움증 억제용 조성물
JP7520810B2 (ja) 医薬製剤
KR101427163B1 (ko) Ｐｄｅ5 억제제를 함유하는 피부 주름 개선용 조성물
US20240307485A1 (en) Ws635 uses thereof in medicine
TW202406553A (zh) 前額纖維化禿髮之治療
JP4477504B2 (ja) 鎮痒剤
WO2023076515A1 (fr) Formulations topiques de deucravacitinib
CZ202244A3 (cs) Heterocyklické purinové deriváty cytokininů, jejich použití při hojení ran a farmaceutické kompozice obsahující tyto deriváty

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22738402

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22738402

Country of ref document: EP

Kind code of ref document: A1