EP3177365A1 - Agonistes de la voie du récepteur ahr ayant une activité sébosuppressive et procédé d'identification desdits agonistes - Google Patents

Agonistes de la voie du récepteur ahr ayant une activité sébosuppressive et procédé d'identification desdits agonistes

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Publication number
EP3177365A1
EP3177365A1 EP15830204.2A EP15830204A EP3177365A1 EP 3177365 A1 EP3177365 A1 EP 3177365A1 EP 15830204 A EP15830204 A EP 15830204A EP 3177365 A1 EP3177365 A1 EP 3177365A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
benzo
chromen
composition
concentration
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP15830204.2A
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German (de)
English (en)
Other versions
EP3177365A4 (fr
Inventor
Jean Hilaire Saurat
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
THESAN PHARMACEUTICALS Inc
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THESAN PHARMACEUTICALS Inc
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Publication date
Application filed by THESAN PHARMACEUTICALS Inc filed Critical THESAN PHARMACEUTICALS Inc
Publication of EP3177365A1 publication Critical patent/EP3177365A1/fr
Publication of EP3177365A4 publication Critical patent/EP3177365A4/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61P17/08—Antiseborrheics

Definitions

  • the present invention relates to triaging or sorting and selecting substances for their capacity for sebosuppressive activity in topical skin treatments.
  • the invention also concerns substances identified from such triaging or sorting.
  • the present invention relates more particularly to a topical pharmaceutical composition for the treatment and/or prevention of hyperseborrhea and associated seborrheic skin disorders such as acne and seborrheic dermatitis.
  • the aryl hydrocarbon Receptor (AhR) is a transcription factor, which induces the expression of some genes while inhibiting the expression of other genes.
  • AhR is typically expressed in epithelial and mesenchymal skin cells, as well as in other cell types (Ikuta et al . 2009) .
  • International Patent Publications WO 2004/041758 and WO 2007/128725 and U.S. Patent Application Publication No. 2009/0028804 Al describe certain in vitro tests to determine the antagonist or agonist nature of such ligands.
  • the prototypical xenobiotic agonist ligand of the AhR is the notorious environmental toxin 2 , 3 , 7 , 8-tetrachlorodibenzo-p-dioxin (TCDD) , better known simply as "dioxin” (Mandal (2005)) .
  • TCDD toxin 2 , 3 , 7 , 8-tetrachlorodibenzo-p-dioxin
  • Other xenotoxic compounds which interact as agonists with the AhR are also capable of causing various types of damaging tissue lesions. Multiple toxic effects are known. The most visible are the cystic lesions formerly called “chloracne” but which have more recently been redefined as MADISH (Saurat et al . (2012)).
  • AhR pathway agonists in a therapeutic and/or preventative context as active agents that beneficially modulate skin function is counter- intuitive .
  • International Patent Publications WO 2004/041758 and WO 2007/128725 propose to use AhR antagonists rather than agonists to treat various dermatological conditions, including acne.
  • U.S. Patent Application Publication No. 2010/0324109 Al suggests that the application to the skin of certain AhR receptor pathway agonists may favorably modulate some skin functions such as sebaceous gland function, acne, defense against infection, wound healing, and skin atrophies which involve dermatoporosis and estrogen deprivation.
  • certain properties must be selected for.
  • This invention provides a novel method to identify sebum reducing AhR pathway agonists useful to treat certain skin diseases, and novel pharmaceutical compositions useful for treating disorders related to abnormal metabolism mediated by the AhR receptor.
  • the subject invention provides a method of treating acne in a subject which comprises topically and periodically applying to the subject's acne a composition comprising 3-phenyl-l-benzo [f] chromen- 1-one and a pharmaceutically acceptable carrier, wherein the 3- phenyl-l-benzo [f] chromen-l-one is present in an amount effective to treat the subject's acne.
  • the subject invention also provides a method of treating a skin condition associated with abnormal sebum secretion or abnormal sebaceous gland function in a subject which comprises topically and periodically applying to an area of subject's skin affected by the skin condition a composition comprising 3-phenyl-l-benzo [f] chromen- l-one and a pharmaceutically acceptable carrier, wherein the 3- phenyl-l-benzo [f] chromen-l-one is present in an amount effective to treat the skin condition.
  • the subject invention also provides a composition comprising 3- phenyl-l-benzo [f] chromen-l-one and a pharmaceutically acceptable carrier, wherein the 3-phenyl-l-benzo [f] chromen-l-one is present at a concentration between about 0.005% and about 5% by weight.
  • Figure 1 provides illustrations (1A, 2A, 3A and 4A) identifying the location inside a sebaceous gland of the four types of sebaceous cells able to express the CYP1A1 gene, namely:
  • Figure 2 shows photomicrographs (1B and C, 2B, 3B and 4B) identifying the four types of cells able to express the CYP1A1 gene, following treatment with Ahr pathway agonists.
  • IB and C show progenitor cells following administration of NSA4 ; 2B shows undifferentiated cells following treatment with NSA1; 3B shows differentiated cells following treatment with NSA2 and 4B shows mature cells following treatment with NSA3.
  • Photograph C shows progenitor cells at a different viewing angle and magnification of the region shown in photograph IB .
  • Figure 3 shows the onset of CYP1A1 activity vs. time in all four sub-populations of sebaceous cells from Figures 1 and 2, after topical application of several ligands of the AhR receptor.
  • the biological effect is defined as the stage of sebaceous cell differentiation, signified by values of 1 to 4 corresponding to stage 1 to 4 of differentiation as discussed above; these effects are affected by exposure to test compounds as indicated in visualization of CYP1A1.
  • Figure 4 shows the inhibition of the transcription of certain genes encoding sebogenic enzymes by three structurally related compounds (NSA-2, NSA-8 and NSA-9) and compared with NSA- 3 (TCDD) .
  • Figure 5 shows the relative surface occupied by the sebaceous glands in the dermis over time, subsequent to treatment with NSA- 2 (3 -phenyl -1-benzo [f] chromen-l-one) at three different concentrations .
  • Figure 6 shows the differentiation index in the sebaceous glands subsequent to treatment with NSA-2 at three different concentrations for a 3 week period (5 application days per week) .
  • Figure 7 shows the number of differentiated and mature sebocytes subsequent to treatment with NSA-2 at three different concentrations .
  • Figure 8 shows the number of active sebaceous glands subsequent to treatment with NSA-2 at three different concentrations.
  • the subject invention provides a method of treating acne in a subject which comprises topically and periodically applying to the subject's acne a composition comprising 3-phenyl-l- benzo [f] chromen-l-one and a pharmaceutically acceptable carrier, wherein the 3 -phenyl-1-benzo [f] chromen-l-one is present in the composition in an amount effective to treat the subject's acne.
  • 3-phenyl-l-benzo [f] chromen-l-one also known as beta-naphthoflavone, is present in the composition at a concentration between about 0.005% and about 5% by weight.
  • 3 -phenyl-1-benzo [f] chromen-l-one is present in the composition at a concentration between about 0.1% and about 2.5% by weight.
  • 3-phenyl-l- benzo [f] chromen-1 -one is present in the composition at a concentration of about 0.1% by weight.
  • 3 -phenyl-1-benzo [f] chromen-l-one is present in the composition at a concentration of about 0.25% by weight, about 0.5% by weight, about 1% by weight, about 2% by weight, or about 5% by weight.
  • the pharmaceutically acceptable carrier comprises ethanol.
  • the pharmaceutically acceptable carrier comprises polyethylene glycol having an average molecular weight between 200 g/mol and 1000 g/mol . In one such embodiment, the polyethylene glycol has an average molecular weight of about 400 g/mol.
  • the pharmaceutically acceptable carrier comprises a mixture of ethanol and polyethylene glycol in a ratio from 5:1 to 1:5 by volume, for example, between 2:1 and 1:2 by volume, particularly about 1:1 by volume.
  • the pharmaceutical composition is a solution and comprises 3-phenyl-l-benzo [f] chromen-l-one at a concentration between 0.005 g and 1.0 g 3-phenyl-l-benzo [f] chromen-l-one per 100 mL of the composition and the pharmaceutically acceptable carrier comprises a mixture of ethanol and polyethylene glycol having an average molecular weight of about 400 g/mol in a ratio of about 1:1 by volume.
  • the concentration of 3 -phenyl-1-benzo [f] chromen-l-one is between 0.05g and 0.5g. In yet another embodiment, the 3 -phenyl-1-benzo [f] chromen-l-one is at a concentration of about 0.5 g, the polyethylene glycol has an average molecular weight of about 400g/mol and the mixture of ethanol and polyethylene glycol is in a ratio of about 1:1 by volume .
  • the pharmaceutically acceptable carrier further comprises one or more of an alcohol, an anti-bacterial agent, a preservative, and a chelating agent.
  • the pharmaceutical composition is in the form of a lotion, gel, cream, ointment, foam, solution, suspension, dispersion or impregnated dressing.
  • the acne is facial acne; in other embodiments chest, back and/or shoulder acne, for example, the acne associated with Propionibacterium acnes or the acne is associated with a high sebum secretion rate.
  • 3 -phenyl-1-benzo [f] chromen-l-one is topically applied daily.
  • 3-phenyl-l- benzo [f] chromen-l-one is topically applied only at night.
  • 3 -phenyl-1-benzo [f] chromen-1 -one is topically applied twice or three times daily.
  • 3 -phenyl-1-benzo [f] chromen-l-one is topically applied every other day.
  • 3-phenyl-l- benzo [f] chromen-l-one is topically applied weekly.
  • the subject invention also provides a method of treating a skin condition associated with abnormal sebum secretion or abnormal sebaceous gland function in a subject which comprises topically and periodically applying to an area of the subject's skin affected by the skin condition a composition comprising 3 -phenyl- 1-benzo [f] chromen-l-one and a pharmaceutically acceptable carrier, wherein the 3 -phenyl-1-benzo [f] chromen-l-one is present in the composition in an amount effective to treat the skin condition.
  • the skin condition may be any of oily skin, oily hair, shiny or greasy-looking skin, hyperseborrhea, seborrheic dermatitis, rosacea, sebaceous hyperplasia or sebaceous carcinoma.
  • the skin condition is seborrheic dermatitis.
  • the skin condition is rosacea.
  • the skin condition is hyperseborrhea, sebaceous hyperplasia, or sebaceous carcinoma.
  • 3 -phenyl-1-benzo [f] chromen-l-one is present in the composition at a concentration between about 0.005% and about 5% by weight.
  • 3 -phenyl-1- benzo [f] chromen-l-one is present in the composition at a concentration between about 0.1% and about 2.5% by weight.
  • 3 -phenyl-1-benzo [f] chromen-l-one is present in the composition at a concentration of about 0.1% by weight, about 0.25% by weight, about 0.5% by weight, about 1% by weight, about 2% by weight, or about 5% by weight.
  • the pharmaceutically acceptable carrier comprises ethanol.
  • the pharmaceutically acceptable carrier comprises polyethylene glycol having an average molecular weight between 200g/mol and lOOOg/mol. In one such embodiment, the polyethylene glycol has an average molecular weight of about 400 g/mol.
  • the pharmaceutically acceptable carrier comprises a mixture of ethanol and polyethylene glycol in a ratio from 5:1 to 1:5 by volume, for example, between 2:1 and 1:2 by volume, particularly about 1:1 by volume.
  • the pharmaceutical composition is a solution and comprises 3 -phenyl-1-benzo [f] chromen-l-one at a concentration between 0.005g and 1. Og 3 -phenyl -1 -benzo [f] chromen-l-one per 100 mL of the composition and the pharmaceutically acceptable carrier comprises a mixture of ethanol and polyethylene glycol having an average molecular weight of about 400 g/mol in a ratio of about 1:1 by volume.
  • the concentration of 3- phenyl-1-benzo [f] chromen-l-one is between 0.05 g and 0.5g. In another embodiment, the ratio is between 2:1 and 1:2 by volume. In one such embodiment, the 3 -phenyl-1-benzo [f] chromen-l-one is at a concentration of about 0.5g, the polyethylene glycol has an average molecular weight of about 400 g/mol and the mixture of ethanol and polyethylene glycol is in a ratio of about 1:1 by volume.
  • the pharmaceutically acceptable carrier further comprises one or more of an alcohol, an anti-bacterial agent, a preservative, and a chelating agent.
  • the pharmaceutical composition is in the form of a lotion, gel, cream, ointment, foam, solution, suspension, dispersion or impregnated dressing.
  • the area of the subject's skin affected by the skin condition is on the face, chest, shoulders or back.
  • the skin condition is associated with Propionibacterium acnes and/or a high sebum secretion rate.
  • 3 -phenyl-1-benzo [f] chromen-l-one is topically applied daily. In other embodiments, 3-phenyl-l- benzo [f] chromen-l-one is topically applied only at night. In still other embodiments, 3 -phenyl-1-benzo [f] chromen-l-one is topically applied twice or three times daily. In still further embodiments, 3-phenyl- 1-benzo [f] chromen-l-one is topically applied every other day. In still other embodiments, 3-phenyl-l- benzo [f] chromen-l-one is topically applied weekly.
  • the subject invention also provides a composition comprising 3- phenyl-1-benzo [f] chromen-l-one and a pharmaceutically acceptable carrier, wherein the 3 -phenyl-1-benzo [f] chromen-l-one is present at a concentration between about 0.005% and about 5% by weight.
  • the 3-phenyl-l-benzo [f] chromen-l-one is present at a concentration between about 0.1% and about 2.5% by weight.
  • the 3-phenyl-l-benzo [f] chromen-l-one is present at a concentration of about 0.1% by weight.
  • the 3-phenyl-l-benzo [f] chromen-l-one is present at a concentration of about 0.25% by weight, about 0.5% by weight, about 1% by weight, about 2% by weight, or about 5% by weight .
  • the pharmaceutically acceptable carrier comprises ethanol.
  • the pharmaceutically acceptable carrier comprises polyethylene glycol having an average molecular weight between 200g/mol and lOOOg/mol. In one such embodiment, the polyethylene glycol has an average molecular weight of about 400 g/mol.
  • the pharmaceutically acceptable carrier comprises a mixture of ethanol and polyethylene glycol in a ratio from 5:1 and 1:5 by volume, for example, between 2:1 and 1:2 by volume, particularly, about 1:1 by volume.
  • the pharmaceutical composition is a solution and comprises 3-phenyl-l-benzo [f] chromen-l-one at a concentration between 0.005 g and 1.0 g 3-phenyl-l-benzo [f] chromen-l-one per 100 mL of the composition and the pharmaceutically acceptable carrier comprises a mixture of ethanol and polyethylene glycol (having an average molecular weight of about 400 g/mol in a ratio of about 1:1 by volume.
  • the concentration of 3- phenyl-l-benzo [f] chromen-l-one is between 0.05 g and 0.5g.
  • the 3-phenyl-l-benzo [f] chromen-l-one is at a concentration of about 0.5g
  • the polyethylene glycol has an average molecular weight of about 400 g/mol and the mixture of ethanol and polyethylene glycol is in a ratio of about 1:1 by volume .
  • the pharmaceutically acceptable carrier further comprises one or more of an alcohol, an anti-bacterial agent, a preservative, and a chelating agent.
  • the pharmaceutical composition is in the form of a lotion, gel, cream, ointment, foam, solution, suspension, dispersion or impregnated dressing.
  • the subject invention also provides a method of predicting clinical responsiveness of a subject to treatment of acne by- topical application of 3 -phenyl -lH-benzo [f] chromen-l-one, the method comprising inducing CYP1A1 expression in the subject and evaluating the amount of CYP1A1 expressed so as to predict the clinical responsiveness of the subject.
  • the amount of CYP1A1 expressed has a positive correlation with clinical responsiveness.
  • the subject invention also provides a method of predicting clinical responsiveness of a subject to treatment of a skin condition associated with abnormal sebum secretion or abnormal sebaceous gland function by topical application of 3-phenyl-lH- benzo [f] chromen-l-one, the method comprising inducing CYP1A1 expression in the subject and evaluating the amount of CYP1A1 expressed to predict the clinical responsiveness of the subject.
  • the skin condition is oily skin, oily hair, shiny or greasy-looking skin, hyperseborrhea, seborrheic dermatitis, rosacea, sebaceous hyperplasia or sebaceous carcinoma.
  • the amount of CYP1A1 expressed has a positive correlation with clinical responsiveness.
  • the subject also relates to a method of triaging or sorting and selecting substances in order to better determine their capacity for sebosuppressive activity in topical or local skin treatments, comprising an in vivo test, the said in vivo test comprising the following steps: a) choosing a substance from amongst sebum reducing AhR pathway agonists ; b) choosing a mammal in which the CYP1A1 gene can be induced in the skin; c) treating a part of the skin of said mammal, chosen in relation to the localization of sebaceous glands thereof, via a topical route, with a composition containing the said substance, following a dose response vs.
  • the said sebum reducing AhR pathway agonists to be tested are preferably chosen from among known AhR agonists or first determined to be an AhR agonist by at least one suitable in vitro test, for example first screening using the CALUX (He et al . 2011) and/or EROD tests (Zamaratskaia et al . (2009), Behnisch et al . (2001),), to determine both potency and the degree of maximum induction, combined with the understanding or demonstration of a short in vivo half-life by standard methods known to those skilled in the art.
  • rodents for this purpose, more preferably the murine C57BL/6 strain.
  • the skin of the ears which are known to contain multiple sebaceous glands, are particularly preferred. Being well suited to this type of analysis they are also a locale where the CYP1A1 gene is likely to be induced.
  • the ears of the said mice are treated via the topical route, then sampled vs. time, and the expression of CYPlAl is examined by immunohistochemical analysis using an antibody.
  • the antibody used may be the rabbit anti-rat CYPlAl polyclonal antibody (Millipore AB1247) .
  • the examination of the expression of CYPlAl in the sebaceous glands may comprise: a) examination of the isthmus region, in particular examination of the progenitor cells (see Jensen et al. 2009, Niemann et al. 2012) ; b) examination of the peripheral regions of the gland, in particular examination of the undifferentiated cells; c) examination of the intermedia region of the gland, in particular examination of the differentiated cells; and/or d) examination of the central region of the gland, in particular examination of the mature cells.
  • the substance is considered active if the said in vivo test exhibits immunohistochemical staining in the plurality of relevant cell types indicated above within a determined time period;
  • the said substance can be selected if the expression of CYPlAl is labeled in at least two cell types after one week's treatment.
  • the said substance is preferably selected if the expression of CYPlAl is labelled in all four cell types after one week's treatment.
  • an object of the invention is a composition for treating and/or preventing skin diseases of a human being, in particular the associated skin conditions of acne, seborrheic dermatitis and rosacea, wherein the composition is able to treat and/or prevent hyperseborrhea by means of topical or local application of said composition on the skin, and composition comprising an active substance selected from the group consisting of AhR pathway agonists having: a) an ability to activate one or more components of the sebum reducing AhR pathway; b) an ability to modulate a gene regulated by the AhR pathway; c) a short half-life in the human organism, either predicted from standard mammalian pharmacokinetic studies or actually determined, of less than 24 hours; preferably less than 4hrs d) a measureable positive effect on a recognized criterion of sebum reduction.
  • AhR pathway agonists having: a) an ability to activate one or more components of the sebum reducing AhR pathway; b) an ability to modulate a
  • a presently preferred embodiment of the invention is rutecarpine, a pharmaceutically acceptable salt of rutecarpine, or an herbal (plant/fruit) extract comprising rutecarpine as the active substance in a sebosuppressive composition for topical use.
  • Another presently preferred embodiment of the invention is 3- phenyl-lH-benzo [f] chromen-l-one, as the active substance in a sebosuppressive composition for topical use.
  • an object of the invention is a method for treating and/or preventing skin diseases of a human being, such as acne, seborrheic dermatitis and rosacea, comprising providing a composition that is able to treat and/or prevent hyperseborrhea by means of topical application of said composition on the skin, said composition comprising an active substance selected from the group consisting of sebum reducing AhR pathway agonists having: a) an ability to act as a sebum reducing AhR pathway agonist; b) an ability to modulate a gene regulated by the AhR pathway; c) a short half -life in the human organism, either predicted from standard mammalian pharmacokinetic studies or actually determined of less than 24 hours; more preferably less than 4 hours ; d) a measureable positive effect on a recognized criterion of sebum reduction; e) and wherein said active substance is positively selected by an in vivo test as defined above; f) and wherein
  • a particular object of the invention is thus a process for treating and/or preventing hyperseborrhea-induced skin conditions in a human being, comprising providing a composition suitable for topical application on the skin, wherein said composition contains 3- phenyl-lH-benzo [f] chromen-l-one as the active substance, and administering said composition topically or locally to said human being.
  • the term "sebaceous glands” refers to microscopic glands in the skin that secrete an oily/waxy matter, called sebum, to lubricate and waterproof the skin and hair of mammals. In humans, they are found in greatest abundance on the face and scalp, though they are distributed throughout all skin sites except the palms and soles.
  • the term “skin” refers to the outer coverage of the body. In humans, it is the largest organ of the integumentary system. The skin has multiple layers of ectodermal tissue and guards the underlying muscles, bones, ligaments and internal organs. Human skin is similar to that of most other mammals, except that it is not protected by fur. Though nearly all human skin is covered with hair follicles, it can appear hairless.
  • the adjective cutaneous means "of the skin” (from Latin cutis, skin) .
  • the term “dermatoporosis” refers to a new concept proposed to cover different manifestations and implications of chronic cutaneous insufficiency/fragility syndrome. This emerging syndrome extends beyond cosmetics and appearance and is considered to be the functional face of skin aging (Kaya et al. (2007) ) .
  • the term “acne” refers to acne vulgaris, a common human skin disease, characterized by areas of skin with seborrhea (scaly red skin) , comedones (blackheads and whiteheads) , papules (pinheads) , nodules (large papules) , pimples, papulopustules and possible scarring.
  • Acne affects mostly skin with the densest population of sebaceous glands; these areas include the face, the upper part of the chest, and the back. Severe acne is inflammatory, but acne can also manifest in non-inflammatory forms. The lesions are caused by changes in pilosebaceous units, skin structures consisting of hair follicle and its associated sebaceous gland, changes that require androgen stimulation.
  • EROD refers to the ethoxyreorufin-O- deethylase (EROD) assay which monitors the induction of the xenobiotic-metabolizing enzyme cytochrome P-450 1A1(CYP1A1) and is a widely used as a reporter for measuring activation of the AhR in vitro (Zamaratskaia et al . (2009), Behnisch et al . (2001),)
  • CALUX Chemical-Activated Luciferase Gene Expression
  • the CALUX Assay is a dioxin screening bioassay categorized as a reporter-gene assay. It has been approved as an official analysis method by the US EPA in 2007 (Method 4435) (He et al . (2011))
  • CYPlAl refers to Cytochrome P450, family 1, subfamily A, polypeptide 1.
  • CYPlAl is a protein that in humans is encoded by the CYPlAl gene.
  • the protein is a member of the cytochrome P450 superfamily of enzymes, CYPlAl is involved in phase I xenobiotic and drug metabolism (e.g., Monostory et al. (2009), Nerbert and Dalton (2006), Zhou et al . (2009) ).
  • treating or “treatment” of any condition, disease or disorder refers, in some embodiments, to ameliorating the disease, disorder, or condition (i.e., arresting or reducing the development of the disease, disorder, or condition, or at least one of the clinical symptoms thereof) .
  • “treating” or “treatment” refers to ameliorating at least one physical parameter, which may or may not be discernible by the subject, including physical parameters that are undesired but not clinically significant.
  • “treating” or “treatment” refers to inhibiting the disease, disorder, or condition, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of physical parameter) or both.
  • “treating” or “treatment” refers to preventing or to delaying the onset of the disease, disorder, or condition.
  • the term "therapeutically effective amount” or “effective amount” means the amount of a composition, compound, therapy, or course of treatment that, when administered to a subject for treating a disease, disorder, or condition, is sufficient to effect such treatment for the disease, disorder, or condition.
  • the “therapeutically effective amount” will vary depending on the composition, the compound, the therapy, the course of treatment, the disease, disorder, or condition, and its severity and the age, weight, etc., of the subject to be treated.
  • sebum reducing AhR pathway agonists are compounds that by activating one or more components of the AhR pathway, are capable of reducing sebum levels in the skin, when applied topically, locally or systemically.
  • the AhR ligands described herein include further forms of the compounds such as pharmaceutically acceptable salts, solvates (including hydrates), amorphous phases, partially crystalline and crystalline forms (including all polymorphs) , prodrugs, metabolites, N-oxides, isotopically- labeled, epimers, pure epimers, epimer mixtures, enantiomers including but not limited to single enantiomers and enantiomeric diastereomers , meso compounds, stereoisomers, racemic mixtures and diasteroisomeric mixtures.
  • AhR ligand compounds described herein having one or more double bonds include cis/trans isomers, E/Z isomers and geometric isomers.
  • AhR ligand compounds described herein can be prepared as pharmaceutically acceptable salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, for example an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base.
  • AhR ligand compounds described herein can also be prepared as pharmaceutically acceptable salts when a basic function present in the parent compound coordinates with a mineral acid or an organic acid.
  • AhR ligand compounds can also be described herein as being prepared as pharmaceutically acceptable complexes or co-crystals whereby the complex or co-crystal confers modified physical properties of solubility, dissolution rate or permeability.
  • the salt forms of the disclosed compounds can be prepared using salts of the starting material or intermediates.
  • the AhR pathway agonist compounds described herein are isotopically-labeled, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • one or more hydrogen atoms are replaced with deuterium.
  • metabolic sites on the compounds described herein are deuterated.
  • substitution with deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half -life or reduced dosage requirements.
  • groups and substituents thereof can be chosen by one skilled in the field to provide stable moieties and compounds. This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.
  • the biological activity triggered by the topical or systemic administration of the ligand should be uniform in all parts of the body which express the receptor, provided that the ligand is diffused in these parts in sufficient quantity and in a non-metabolized active form, such as seen with the retinoic acid receptor (RAR) or the vitamin D receptor (Milde et al (1991) ; Reichrath et al (1997) ) .
  • RAR retinoic acid receptor
  • vitamin D receptor Vitamin D receptor
  • the application of AhR pathway agonist to the skin should activate the biochemical pathways linked to this receptor uniformly, first in the surface layers of the epidermis, and then progressively, correlating with the entry gradient of the ligand into the deeper layers of the epidermis, possibly the dermis and adnexa, hairs and sebaceous glands. It is known that the AhR receptor is expressed in all these compartments of the skin ( Ikuta et al. 2009) .
  • the ligands endowed with the strongest sebosuppressive activity are those which, without necessarily being the most active during in vitro activation tests of the AhR receptors, follow this sequence of activation in situ at an early stage, rapidly and completely as shown by Tables 1 and 2.
  • the embodiment described here entails treating the ears of C57BL/6 mice via the topical route, following established protocols to determine dose-response and time-response relationships, with sebum reducing AhR pathway agonists previously characterized for their in vivo activation of the receptor, using, for example the EROD and CALUX methods which are widely used in this field (see Table 1) .
  • Table 1 shows the correlations between in vitro tests, in vivo tests according to the invention, and clinical examination of the subosupressive activity in man of the ligands from Figure 3.
  • CYP1A1 expression is examined by immunohistochemical analysis using a specific antibody.
  • NSA2 was used at a concentration of 37 mM
  • NSA4 was used at 35 uM
  • NSA1 at 12mM
  • NSA3 at 6.2 ⁇ .
  • Photomicrographs were taken on a Zeiss microscope at a magnification of 250-fold for photos IB, 2B, 3B, 4B of Figure 2 and at a magnification of 400-fold for Part 1C of the Figure.
  • Figure 1 shows diagrammatically the different types of labelling observed.
  • a positive result from immunohistochemistry i.e. the cells stained brown as would be shown in color originals of the black and white illustrations of Figure 2, indicates that the region expresses the CYP1A1 protein.
  • Results are summarized as follows : a) In the basal state the CYP1A1 protein is not detectable. b) In every case in which the AhR pathway agonists were used, it led to positive staining by CYP1A1 immunohistochemistry. The first region in time to be stained, indicating an increase in the CYP1A1 protein induced by activation of the
  • AhR receptor is the region of the isthmus where the progenitor cells of the sebaceous glands are located ( Figure 1-lA and Figure 2 - 1B) .
  • Stage 1 corresponds to multi-potent clonogenic cells, in other words to the sebaceous stem cells (Frances D and
  • Stage 2 is the extension of CYP1A1 staining to undifferentiated cells which do not contain lipids and in general are located on the periphery of the sebaceous gland ( Figure 1 - 2A and Figure 2 - 2B) .
  • Stage 3 is the further extension of CYP1A1 staining to differentiated cells which contain lipids and are in general located at the intermediate part of the sebaceous gland
  • Stage 4 is the further extension of CYP1A1 staining to mature cells which contain lipids and in general are located at the central part of the sebaceous gland ( Figure 1 - 4A and Figure 2 - 4B) . Correlation between the sequential activation stages and the sebosuppressive properties of the ligand.
  • Table 1 indicates the correlation between the stages of focal activation expression, the index of sebum inhibition, and the effect on human skin.
  • the sebum inhibition index is calculated by counting the number of mature and differentiated cells in relation to the total number of cells in the sebaceous glands. A decrease in mature and differentiated cells indicates blocking of sebogenesis.
  • the effect on human skin is determined by sebumetric examination using what is known as the "casual level" (Dobrev (2007) ) .
  • NSA1 8, 13-Dihydroindolo [2 ' , 3 ' : 3 , 4] pyrido [2 , 1-b] quinazolin- 5(7H)-one (rutecarpine)
  • NSA2 3 -phenyl-1H-benzo [f] chromen-l-one
  • NSA3 2 , 3 , 7, 8 -tetrachlorodibenzo-p-dioxin (TCDD)
  • NSA4 6-formylindolo[3,2-b]carbazole(FICZ) e)
  • NSA5 2- [ (E) -2- (3 , 4 -dihydroxyphenyl ) ethenyl] -6-hydroxypyran- 4-one (Hispidine)
  • NSA6 9H- ⁇ -carboline (Be
  • FIG. 3 A comparison between Figure 3 and Table 1 shows that two AhR pathway agonists, namely NSA-2 (3-phenyl-lH-benzo [f] chromen-l-one) and NSA-3 (TCDD) , which activate the AhR pathway in the four cell sub-populations within a period of less than one week, are also those which display the strongest sebosuppressive activity in man.
  • NSA-2 3-phenyl-lH-benzo [f] chromen-l-one
  • TCDD NSA-3
  • NSA-1 Rutecarpine
  • NSA-7 which only activates the AhR receptor pathways in Stage One of the cell sub-populations, shows no sebosuppressive activity in man, even at 8%, even though its ability to activate AhR in vitro appears similar to NSA-2.
  • NSA-2 (3 -phenyl-lH-benzo [f] chromen-l-one) demonstrates agonist activity in the sebaceous glands in a similar manner to the most active AhR agonist (TCDD) , while 2 -phenyl -4H-benzo [h] chromen-4- one and 2 -phenyl -4H-chromen-4-one do not have these effects.
  • Table 2 shows the activity of TCDD and three other compounds (NSA-2, NSA-8 and NSA-9) in both cell based in vitro tests and in vivo tests according to the invention.
  • Figure 4 shows the results of experiments in which the ears of C57BL/6 mice were treated with the three different compounds (NSA-2, NSA-8 and NSA-9) above at 0.5% in acetone for five weeks.
  • the reference substance positive control
  • RNA RNA corresponding to three major enzymes (fatty acid desaturase 2 [FADS2] , acyl-CoA wax alcohol acyltransferase 1 [AWAT1] , and elongation of very long chain fatty acids protein 3 [ELOV3] in the production of sebaceous lipids.
  • FADS2 fatty acid desaturase 2
  • AAT1 acyl-CoA wax alcohol acyltransferase 1
  • ELOV3 very long chain fatty acids protein 3
  • Figure 4 shows that among the three structurally related compounds tested (NSA-2, NSA-8 and NSA-9) only NSA-2 induced major inhibition of the mRNA expression encoding the three enzymes, whereas NSA-8 had a slightly stimulating effect whilst NSA-9 had no significant effect.
  • NSA-2 strongly inhibited in mice the expression of the genes of key enzymes involved in the production of lipids characteristic of sebum such as AWAT1, ELOVL3 , and FADS2 , which at least partly accounts for the sebosuppressive effects of this compound.
  • the degree of specific gene suppression seen with NSA-2 is equivalent to that seen with the structurally unrelated compound NSA-3 (TCDD) .
  • TCDD can act as a pM agonist of AhR and has a half-life measureable in years.
  • NSA-2 has a half-life in rodents reported at less than 45 mins (Adedoyin et al . (1993)) .
  • NSA-2 as measured in the standard EROD assay, only activates AhR to 10-20% of the level of induction seen with ⁇ . ⁇ TCDD.
  • mice were treated for three to five weeks, five days per week on the ears and in three concentrations, namely 0.1, 0.5, and 1% of NSA-2.
  • the sebosuppressive effect was analyzed at the third week although expression thereof starts after one week.
  • Figures 5-8 show very marked effects which few substances other than TCDD are able to induce in this model- both regarding the total number of active sebaceous glands (Figure 8) , the relative surfaces occupied by the sebaceous glands ( Figure 5) and the ratios between non-differentiated, differentiated and mature sebocytes ( Figure 6 and Figure 7) .
  • This invention allows the rapid selection of candidate sebosuppressive molecules for therapeutic ' use in treating or preventing acne, seborrheic dermatitis and rosacea.

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Abstract

La présente invention concerne un procédé de traitement de l'acné chez un sujet qui consiste à appliquer de manière topique et périodique à l'acné du sujet une composition comprenant du 3-phényl-1-benzo [f] chromène-1-one et un support pharmaceutiquement acceptable, le 3-phényl-1-benzo [f] chromène -1-one étant présent dans une quantité efficace pour traiter l'acné du sujet. La présente invention concerne également un procédé de traitement de l'état d'une peau associé à une sécrétion anormale de sébum ou à une fonction anormale des glandes sébacées chez un sujet, les compositions dans de tels procédés et un procédé de tri permettant d'identifier des agonistes de la voie AhR utiles dans de tels procédés et de telles compositions.
EP15830204.2A 2014-08-06 2015-08-05 Agonistes de la voie du récepteur ahr ayant une activité sébosuppressive et procédé d'identification desdits agonistes Withdrawn EP3177365A4 (fr)

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LU84491A1 (fr) * 1982-11-26 1984-06-13 Oreal Composition anti-acneique contenant en tant que compose actif un derive d'isothiazolo-(5,4b) pyridine one-3
US6008254A (en) * 1997-05-09 1999-12-28 Kligman; Douglas E. Method of treating skin disorders with high-strength tretinoin
US7604821B2 (en) * 2002-07-01 2009-10-20 Maria Villani Porifera-based therapeutic compositions for treating and preventing skin diseases
EP2082736A1 (fr) * 2008-01-23 2009-07-29 Jean Hilaire Saurat Composition pharmaceutique à usage topique
US20120328670A1 (en) * 2011-06-03 2012-12-27 Allergan, Inc. Targeted Delivery of Retinoid Compounds to the Sebaceous Glands
EP2664919A1 (fr) * 2012-05-15 2013-11-20 Jean Hilaire Saurat Une méthode pour identifier les ligands du récepteur AhR possédant une activité sebosuppressive thérapeutique

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