Compositions and methods for treating hair and skin conditions related to folliculopilosebaceous units

Abstract

Disclosed herein are compositions and methods for treating hair and skin conditions related to abnormal folliculopilosebaceous (FPS) units. In some embodiments, the hair and skin conditions related to abnormal FPS units may comprise pseudofolliculitis barbae (PFB), acne keloidalis nuchae (AKN), hidradenitis suppurativa (HS), dissecting cellulitis of the scalp (DCS), acne vulgaris, combinations thereof or associated pigmentary changes related thereto. The compositions of the disclosure comprise an effective amount of a compound used for treating the hair or skin condition related to abnormal FPS units.

Description

Attorney Docket No.206314-0002-WO01 COMPOSITIONS AND METHODS FOR TREATING HAIR AND SKIN CONDITIONS RELATED TO FOLLICULOPILOSEBACEOUS UNITS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No.63 / 579,923 filed on August 31, 2023, which is hereby fully incorporated by reference. FIELD

[0001] This disclosure relates to compositions and methods for treating hair and skin conditions related to abnormal folliculopilosebaceous (FPS) units. The hair and skin conditions may include pseudofolliculitis barbae (PFB), acne keloidalis nuchae (AKN), hidradenitis suppurativa (HS), dissecting cellulitis of the scalp (DCS), and acne vulgaris. The compositions of the disclosure comprise an effective amount of a compound used for treating the hair and skin conditions related to abnormal FPS units. BACKGROUND

[0002] An unmet need is effective treatments for hair and skin conditions related to abnormal folliculopilosebaceous (FPS) units. Abnormalities or unique properties of the FPS unit are the source of many dermatological conditions including hair overgrowth, hair loss, and conditions related to hair shaft abnormalities. There are hair and skin conditions related to abnormal FPS units where decreasing or inhibiting hair growth or decreasing the diameter of hairs in a particular area could be of value to patients. SUMMARY OF THE INVENTION

[0003] In an aspect, the disclosure relates to a method of treating a hair or skin condition related to abnormal folliculopilosebaceous (FPS) units, the method comprising administering to a subject in need thereof, a safe and effective amount of a compound described herein. In an embodiment, the hair or skin condition related to abnormal FPS units comprises pseudofolliculitis barbae (PFB), acne keloidalis nuchae (AKN), hidradenitis suppurativa (HS), dissecting cellulitis of the scalp (DCS), acne vulgaris, or combinations thereof, or associated pigmentary changes related thereto. In another embodiment, the compound is an FP receptor antagonist. In another embodiment, the FP receptor antagonist is selected from the group including OBE002, OBE022, and BAY-6672. In another embodiment, the FP receptor antagonist is a compound of formula (II), or a pharmaceutically acceptable salt thereof,Attorney Docket No.206314-0002-WO01tert-butyl or phenyl, wherein the phenyl is optionally substituted with 1-3 R1a; R1a, at each occurrence, is independently C1-4alkyl, C1-4fluoroalkyl, halogen, cyano, –OC1-4alkyl, or –OC1-4fluoroalkyl; R2is –C1-4alkylene–OH, –C1-4alkylene–OC1-4alkyl; –C1-4alkylene–OC(O)C1-4alkyl, or –C1-4alkylene– OC(O)CH(NH2)R2a; R2ais hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl, –C1-4alkylene–C3-6cycloalkyl, –C1-4alkylene–OH, or –C1-4alkylene–OC1-4alkyl; R3, at each occurrence, is independently C1-4alkyl, C1-4fluoroalkyl, halogen, cyano, –OC1-4alkyl, or –OC1-4fluoroalkyl; R4, at each occurrence, is independently C1-4alkyl or C1-4fluoroalkyl; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4. In another embodiment, the FP receptor antagonist is a compound of formula (III), or a pharmaceutically acceptable salt thereof,(III) wherein: Ar is phenyl or pyridinyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents, the pyridinyl is unsubstituted or substituted with 1-2 substituents, and the substituents are independently selected from the group consisting of fluoro, chloro, C1-4alkyl, C3-4cycloalkyl, –OC1-2alkyl, –SC1-2alkyl, C1-4alkyl substituted by 1-3 fluoro, C3-4cycloalkyl substituted by 1-4 fluoro, –OC1-2alkyl substituted by 1-3 fluoro, –SC1-2alkyl substituted by 1-3 fluoro, or where two substituents of the phenyl or pyridinyl on adjacent ring atoms together form a methylenedioxy or ethylenedioxy; L is a bond or –X– (CRaRb)k–; X is a bond, CH2, O, S, S(O), S(O)2, or N(R); R is hydrogen or CH3; Raand Rbare independently hydrogen, fluoro, or CH3; or Raand Rbtogether with the carbon atom to which they attach form a cyclopropyl; k is 1, 2, 3, or 4; R10is halogen, C1-4alkyl, C1-4alkyl substituted by 1-5 fluoro, –OCH3, –OCH2F, –OCHF2, –OCF3, –SCF3, –SF5, –SiCH3, ethynyl, cyclopropyl, or cyclobutyl, where the cyclopropyl and cyclobutyl are unsubstituted or substituted by 1-4 fluoro; R20, R30, and R40are independently hydrogen, halogen, CH3, CH2F, CHF2, or CF3; R50is halogen, C1-4alkyl, C1-4alkyl substituted by 1-5 fluoro, –OCH3, –OCH2F, –OCHF2, –OCF3, OH, –Attorney Docket No.206314-0002-WO01 SCH3, –SCF3, cyano, ethenyl, cyclopropyl, or cyclobutyl, where the cyclopropyl and cyclobutyl are unsubstituted or substituted by 1-4 fluoro; R60is –NRcRd; Rcis hydrogen or C1-3alkyl; Rdis C1-4alkyl, C3-7cycloalkyl, C1-4alkyl substituted by 1-5 fluoro, C1-4alkyl monosubstituted by C3-6cycloalkyl, –OCH3, –OCF3, or phenyl, wherein the C3-7cycloalkyl is optionally substituted with 1- 4 fluoro; or Rcand Rdtogether with the nitrogen to which they attach form a saturated or partially unsaturated 4- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocyclic ring, the heterocyclic rings optionally containing a ring member selected from the group consisting of O, N, S, SO, and S(O)2, wherein the heterocyclic rings are optionally substituted with 1-4 substituents independently selected from the group consisting of fluoro, C1-4alkyl, OH, oxo, –OC1-3alkyl, –OCHF2, –OCF3, cyano, NH2, NHCH3, N(CH3)2, C(O)NH2, C(O)NHCH3, C(O)N(CH3)2, C1-4alkyl substituted with 1-5 fluoro, and C1-4alkyl monosubstituted with OH or – OCH3; R70Aand R70Bare independently hydrogen or CH3, or R70Aand R70Btogether with the carbon atom to which they attach form a cyclopropyl; R80is hydrogen, fluoro, CH3, CF3, CH2CH3, or OH; and R90is hydrogen or CH3. In another embodiment, the FP receptor antagonist is a compound of formula (IV) or formula (V):wherein R is selected from the group consisting of CO2H, C(O)NHOH, CO2R1, CH2OH, S(O)2R1, C(O)NHR1, P(O)(OR1) R2, C(O)NHS(O)2R1, and tetrazole; R1and R2are independently selected from the group consisting of a hydrogen atom, monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, aromatic groups, substituted aromatic groups, carbocyclic groups, substituted carbocyclic groups, heterogeneous groups, substituted heterogeneous groups, heterocyclic groups, substituted heterocyclic groups, heteroaromatic groups, and substituted heteroaromatic groups; W is -CH2-, -O-, or -S(O)2-; and X is halogen, lower alkyl, alkoxy, or hydrogen. In another embodiment, R1and R2are selected from the group consisting of CH3, C2H5, and C3H7. In another embodiment, R is selected from the group consisting of CO2H, CO2CH3, C(O)NHC2H5, CO2C2H5, CO2C3H7, CO2C4H9, CO2C3H7O2, and C(O)NHS(O)2R1. In another embodiment, R is selected from the group consisting of CO2H, CO2CH3, CO2C2H5, C(O)NHC2H5, and CO2C3H7. In another embodiment, R is selected from the group consisting of CO2H, CO2CH3, C(O)NHC2H5, and CO2C3H7. In another embodiment, X is methoxy. In another embodiment, X is methyl. In another embodiment, X is halogen. InAttorney Docket No.206314-0002-WO01 another embodiment, X is F. In another embodiment, the compound is a 11-deoxy-16-fluoro PGF2αanalog. In another embodiment, the compound is the following:. In another embodiment, the compound is the following:. In another embodiment, the FP receptor antagonist is a compound of formula (VI):wherein G is selected from the group consisting of substituted or unsubstituted C1-C6-alkyl aryl, substituted or unsubstituted C1-C6-alkyl heteroaryl,Attorney Docket No.206314-0002-WO01 substituted or unsubstituted C1-C6-alkyl cycloalkyl, substituted or unsubstituted C1-C6-alkyl heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, wherein said cycloalkyl or aryl or heteroaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups; R1is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, wherein said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (hetero)-cycloalkyl or aryl or heteroaryl groups; R2is H, carboxy, acyl, alkoxycarbonyl, aminocarbonyl, substituted or unsubstituted C1-C5-alkyl carboxy, substituted or unsubstituted C1-C5-alkyl acyl, substituted or unsubstituted C1-C5-alkyl alkoxycarbonyl, substituted or unsubstituted C1-C5-alkyl aminocarbonyl, substituted or unsubstituted C1-C5-alkyl acyloxy, substituted or unsubstituted C1-C5-alkyl acylamino, substituted or unsubstituted C1-C5-alkyl ureido, substituted or unsubstituted C1-C5-alkyl amino, substituted or unsubstituted C1-C5-alkyl alkoxy, substituted or unsubstituted C1-C5-alkyl sulfanyl, substituted or unsubstituted C1-C5-alkyl sulfinyl, substituted or un substituted C1-C5-alkyl sulfonyl, substituted or unsubstituted C1-C5-alkyl sulfonylamino, substituted or unsubstituted C1-C5-alkyl sulfonyloxy, substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C1-C6-a1kyl aryl, substituted or unsubstituted C2-C6-alkyl heteroaryl, substituted or unsubstituted C1-C6-alkyl cycloalkyl, substituted or unsubstituted C1-C6-alkyl heterocycloalkyl, substituted or unsubstituted C2-C6-alkenyl aryl, substituted or unsubstituted C2-C6-alkenyl heteroaryl, substituted or unsubstituted C2-C6-alkynyl aryl, or substituted or unsubstituted C2-C6- alkynyl heteroaryl, or wherein R2and G may form a C3-C8-cycloalkyl ring; R4is selected from the group consisting of substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted C2- C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl; and n is an integer from 0 to 2. In another embodiment, G is an aryl group. In another embodiment, G is a substituted or unsubstituted phenyl. In another embodiment, G is a biphenyl. In another embodiment, the compound is the following:Attorney Docket No.206314-0002-WO01. In another embodiment, the FP receptor antagonist is a compound of formula (VII): Y- AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-Z (VII) wherein Y is attached to the amino-terminus of said peptide and is selected from the group consisting of a hydrogen atom, an acetyl group, a benzoyl group, an acyl group (R--CO--) wherein R is a hydrophobic moiety, and an aroyl group (Ar--CO--) wherein Ar is an aryl group; AA1 and AA2 are independently selected from the group consisting of no residue, isoleucine (Ile), leucine (Leu), and related alpha-amino acids possessing hydrophobic side-chains; AA3is selected from the group consisting of no residue, glycine (Gly), alanine (Ala), and proline (Pro); AA4 is selected from the group consisting of histidine (His), phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp); AA5is selected from the group consisting of arginine (Arg), ornithine (Orn), lysine (Lys), citruline, 2-, 3-, and 4- pyridylalanine, and arginine surrogates; AA6is selected from the group consisting of aspartic acid (Asp), asparagine (Asn), glutamic acid (Glu), glutamine (Gln), serine (Ser), 3-amino-5- phenylpentanoic acid, and Phe; AA7is selected from the group consisting of no residue, Tyr, and Phe; AA8is selected from the group consisting of no residue, Lys, Leu, and Tyr; and Z is attached to the carboxy-terminus of said peptide and is selected from the group consisting of, a hydroxyl group, NH2, and aromatic and aliphatic amines. In another embodiment, the FP receptor antagonist comprises a polypeptide of SEQ ID NO: 1. In another embodiment, the FP receptor antagonist is a compound of formula (VIII): Y-BTM-AA1-AA2-AA3-Z (VIII) wherein Y is attached to the amino-terminus of the peptide and is selected from the group consisting of a hydrogen atom, an acyl group (R--CO--) wherein R is a hydrophobic moiety, and an aroyl group (Ar--CO--) wherein Ar is an aryl group; BTM (beta turn mimetic) is a dipeptide surrogate; AA1is selected from the group consisting of Arg, Orn, Lys, citruline, 2-, 3-, and 4-pyridylalanine, and arginine surrogates; AA2is selected from the group consisting of Asp, Asn, Glu, Gln, Ser, 3- amino-5-phenylpentanoic acid, and Phe; AA3is selected from the group consisting of no residue, Tyr, and Phe; and Z is selected from the group consisting of no residue, a hydroxyl group, NH2, and aromatic, heteroaromatic, and aliphatic amines.Attorney Docket No.206314-0002-WO01 In another embodiment, the compound is an ornithine decarboxylase inhibitor selected from the group including 2-(difluoromethyl)-2,5-diaminopentanoic acid; alpha-ethynyl ornithine; 6- heptyne-2,5-diamine; and 2-methyl-6-heptyne diamine. In another embodiment, the ornithine decarboxylase inhibitor is eflornithine hydrochloride. In another embodiment, 0.0001 g to about 25.0 g of the compound is administered to the subject per day. In another embodiment, the compound is topically or orally administered to the subject. In another embodiment, the compound is administered to the subject in one or more of an intralesional injection, shampoo, lotion, solution, oil, cream, ointment, gel, leave-on and rinse-out hair conditioners, milk, cleanser, moisturizer, mousse, spray, foam, skin patches, or the like. In another embodiment, the compound is administered to the subject’s scalp, eyebrows, beard, moustache, body hair, skin, or combinations thereof. In another embodiment, the compound is administered for about 6 weeks to about 10 weeks. In another embodiment, PFB is treated in the subject. In another embodiment, AKN is treated in the subject. In another embodiment, HS is treated in the subject. In another embodiment, DCS is treated in the subject. In another embodiment, acne vulgaris is treated in the subject. In another embodiment, associated pigmentary changes related to the preceding conditions are treated in the subject. In another embodiment, the compound inhibits or decreases hair growth in the subject. In another embodiment, the compound decreases the diameter of hairs in the subject.

[0004] The disclosure provides for other aspects and embodiments that will be apparent in light of the following detailed description. DETAILED DESCRIPTION

[0005] Methods are provided herein for treating hair and skin conditions related to abnormal folliculopilosebaceous (FPS) units comprising administering compounds as described herein to a subject in need thereof. The hair and skin conditions related to abnormal FPS units may comprise pseudofolliculitis barbae (PFB), acne keloidalis nuchae (AKN), hidradenitis suppurativa (HS), dissecting cellulitis of the scalp (DCS), acne vulgaris (and all associated acne subtypes including comedonal, papulopustular, nodular, and acne conglobate), or combinations thereof or the pigmentary changes related to these conditions. This disclosure relates to compositions comprising compounds to treat the hair and skin conditions related to abnormal FPS units. The compounds and methods as described herein may treat the hair and skin conditions related to abnormal FPS units by decreasing or inhibiting hair growth and / or decreasing the diameter of hairs in particular areas of a subject or decreasing or reducing the accompanying pigmentation changes caused by these conditions.Attorney Docket No.206314-0002-WO01

[0006] In some embodiments, the compounds may comprise one or more prostaglandin FP receptor antagonists (e.g., prostaglandin F receptor antagonists) or selective modifiers of the FP ligand to treat hair and skin conditions related to abnormal FPS units. The prostaglandin antagonist may interact strongly with hair-selective receptors, such as the FP receptor. The prostaglandin analog may selectively inhibit activation of the FP receptor and not activate any other receptors that would negate the effect of inhibiting the FP receptor. In some embodiments, the compounds may comprise one or more ornithine decarboxylase inhibitors (e.g., eflornithine; eflornithine hydrochloride) to treat hair and skin conditions related to abnormal FPS units. In some embodiments, the compounds may comprise one or more prostaglandin FP receptor antagonists and one or more ornithine decarboxylase inhibitors to treat hair and skin conditions related to abnormal FPS units.

[0007] Publications and patents are referred to throughout this disclosure. All U.S. patents and publications cited herein are hereby incorporated by reference in their entireties.

[0008] All percentages, ratios, and proportions used herein are by weight unless otherwise specified.

[0009] In the description, various embodiments and individual features are disclosed. As will be apparent to a person having ordinary skill in the art, all combinations of such embodiments and features are possible and can result in preferred embodiments of the invention. 1. Definitions

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entireties. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0011] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.Attorney Docket No.206314-0002-WO01

[0012] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9- 1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0013] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0014] As used herein, the terms “administering,” “providing” and “introducing” are used interchangeably herein and refer to the placement of the compounds of the disclosure into a subject by a method or route that results in at least partial localization of the compound to a desired site. The compounds can be administered by any appropriate route which results in delivery to a desired location in the subject.

[0015] As used herein, the terms “effective amount” or “therapeutically effective amount,” refer to a sufficient amount of an agent or a composition or combination of compositions being administered which will relieve or prevent to some extent one or more of the signs or symptoms of the disease or condition being treated. The result can be reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant change (decrease or increase) in condition symptoms, dependent on goal of treatment. An appropriate “effective” amount in any individual case may be determined using techniques, such as a dose escalation study. The dose could be administered in one or more administrations. However, the precise determination of what would be considered an effective dose may be based on factors individual to each patient, including, but not limited to, the patient’s age, BMI,, type or extent of condition, stage of the condition, route of administration, the type or extent of supplemental therapy used, ongoing condition process and type of treatment desired (e.g., aggressive vs. conventional treatment).

[0016] As used herein, “folliculopilosebaceous unit” or “FPS unit” refers to a dermatological structure that includes all of the components necessary to produce a hair follicle, the associated hair shaft and its pigment, and the associated sebaceous gland. The contents of theAttorney Docket No.206314-0002-WO01 sebaceous gland open into the follicular duct. An “abnormal FPS unit” refers to an FPS unit having abnormal, unique, and / or deficient structural and / or functional characteristics which may result in one or more dermatological conditions including hair overgrowth, hair loss, abnormal hair shaft size, orientation, and / or pigmentary changes or erratic growth, and other hair and skin conditions related to hair shaft abnormalities. Various hair and skin conditions related to abnormal FPS units are described herein.

[0017] As used herein, “pseudofolliculitis barbae” or “PFB” refers to a hair and skin condition related to abnormal FPS units. PFB is a cutaneous condition that typically develops as a result of the removal of facial hair and is commonly referred to as "razor bumps," "shave bumps," or "ingrown hairs.” Clinical findings have indicated that PFB may result from a cutaneous, inflammatory reaction against hair that has penetrated the interfollicular skin. This usually occurs when the hair has been cut flush with the skin and the emerging hair penetrates the skin either before or after exit from the end of the follicular orifice. PFB is most common among patients of African ancestry as the hair shafts have a greater tendency to curve back towards the surface of the skin upon emerging from the hair canal. This can then lead to papules and pustules that are most commonly located on the anterior neck, mandible, cheeks, and chin. Further, individuals who remove hair from sites such as the axilla, pubic area, and legs may develop PFB in these areas. Post inflammatory hyperpigmentation, secondary bacterial infection, scarring, and keloid formation are potential complications associated with PFB. Conventional treatments include laser hair removal, electrolysis, depilatory creams, and other treatments for removing or inhibiting hair growth. In addition, shaving methods or razors that prevent cutting the hair flush to the skin can help to prevent PFB. Agents that help with the accompanying inflammation and hyperpigmentation may be useful adjuvants.

[0018] As used herein, “acne keloidalis nuchae” or “AKN” refers to a hair and skin condition related to abnormal FPS units. Specifically, acne keloidalis nuchae (AKN) relates to a chronic inflammatory condition of the FPS units leading to keloid-like papules and plaques and scarring alopecia. Acne keloidalis nuchae is also known as “acne keloidalis,” “folliculitis keloidalis,” “folliculitis keloidalis nuchae,” “sycosis framboesiformis,” and “dermatitis papillaris capillitii.” Acne keloidalis nuchae commonly involves the posterior inferior scalp and neck and is most common among African American males. Clinically, AKN manifests as inflamed papules or pustules that eventuate into keloidal papules or plaques. The exact cause of AKN is unclear, but a role of close cutting the hair and penetration of curved hair into the skin, much like PFB, has been suggested. Another theory is that intrafollicular antigens incite inflammation that leads to follicular injury, penetration of the follicular wall by the hair shaft, and hypertrophic scarring. First line treatment typically involves discontinuing close shaving at the affected area in combination with topical or intralesional steroids. Topical or oral antibiotics and topical orAttorney Docket No.206314-0002-WO01 oral retinoids are also used, as is destruction of the FPS unit by laser, surgical excision, or radiation.

[0019] As used herein, “hidradenitis suppurativa” or “HS” (also called acne inversa) refers to a hair and skin condition related to abnormal FPS units. HS is a chronic, painful, follicular occlusive disease that affects the FPS unit primarily, but not exclusively, in intertriginous axillary, groin, perianal, perineal, genital, and inframammary skin. The clinical course of HS is highly variable, ranging from papules, pustules, and inflammatory nodules to deep, fluctuant abscesses, and draining sinuses. Conventional interventions that exist for HS treatment include topical therapies, oral therapies, biologic therapies, and ultraviolet light. Treatments that decrease hair growth are also helpful for this condition. One primary treatment for HS includes a 5-alpha reductase inhibitor (e.g., finasteride or dutasteride) that functions by decreasing the conversion of testosterone to dihydrotestosterone (DHT) and decreasing androgen related hair growth. These medications are also helpful in pattern hair loss and hirsutism. In addition, laser hair removaland surgical removal of the involved FPS unit with its associated sebaceous glands in affected areas of HS have been shown to reduce disease severity.

[0020] As used herein, “dissecting cellulitis of the scalp” or “DCS” refers to a hair and skin condition related to abnormal FPS units. DCS is also commonly known as perifolliculitis capitis abscedens et suffodiens or Hoffman disease and is considered to involve follicular occlusion of the FPS unit as a key pathogenic event. DCS typically manifests as boggy, suppurative nodules on the scalp with associated sinus formation and patchy hair loss. The hairs in these areas are engulfed in this chronic inflammatory process. In DCS patients refractory to medical therapies such as antibiotics and systemic anti-inflammatory agents, procedures to remove the hairs in the affected areas such as laser-assisted epilation or ablation, X-ray epilation, or surgical excision may be helpful.

[0021] As used herein, “acne vulgaris” or “acne” refers to a hair and skin condition related to abnormal FPS units, and includes all associated acne subtypes including, but not limited to, comedonal, papulopustular, nodular, and acne conglobate. Acne vulgaris is an inflammatory disorder of the FPS unit. Acne vulgaris may present with small papules or papulopustules, large draining lesions, sinus tracts, and scarring in the variant called acne conglobate. The pathogenesis of acne involves a complex interplay of factors including androgens, the local microbiome, immune reactions, and genetic contributions. Although rarely used as a frontline treatment, conventional laser treatment has been shown to be helpful due to its effect on hair inhibition and sebaceous gland function. Spironolactone, an antiandrogen that inhibits binding to the androgen receptor, is a useful treatment for acne vulgaris, excess hair growth (hirsutism) and pattern hair loss, and all androgen-sensitive conditions. Topical or systemic antibiotics,Attorney Docket No.206314-0002-WO01 topical or systemic retinoids, topical antiandrogens, topical benzoyl peroxide, topical azaleic acid, topical salicylic acid, topical dapsone are other commonly used treatments for acne vulgaris.

[0022] The term “alkyl,” as used herein, means a straight or branched, saturated hydrocarbon chain. The term “lower alkyl” or “C1-6alkyl” means a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. The term “C1-4alkyl” means a straight or branched chain hydrocarbon containing from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0023] The term “alkylene,” as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon, for example, of 1 to 3 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- , and -CH2CH2CH2CH2CH2-.

[0024] The term “cycloalkyl” or “cycloalkane,” as used herein, refers to a saturated ring system containing all carbon atoms as ring members and zero double bonds. The term “cycloalkyl” is used herein to refer to a cycloalkane when present as a substituent. A cycloalkyl may be a monocyclic cycloalkyl (e.g., cyclopropyl), a fused bicyclic cycloalkyl (e.g., decahydronaphthalenyl), or a bridged cycloalkyl in which two non-adjacent atoms of a ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms (e.g., bicyclo[2.2.1]heptanyl). A C3-6cycloalkyl is monocyclic. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, and bicyclo[1.1.1]pentanyl.

[0025] Terms such as “alkyl,” “cycloalkyl,” “alkylene,” etc. may be preceded by a designation indicating the number of atoms present in the group in a particular instance (e.g., “C1-4alkyl,” “C3-6cycloalkyl,” “C1-4alkylene”). These designations are used as generally understood by those skilled in the art. For example, the representation “C” followed by a subscripted number indicates the number of carbon atoms present in the group that follows. Thus, “C3alkyl” is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl). Where a range is given, as inthe members of the group that follows may have any number of carbon atoms falling within the recited range. A “C1-4alkyl,” for example, is an alkyl group having from 1 to 4 carbon atoms, however arranged (i.e., straight chain or branched).

[0026] The term “acyl” or “acyl group,” as used herein, means a monovalent group suitable for acylating a nitrogen atom to form an amide or carbamate or an oxygen atom to form an ester group. Preferred acyl groups include benzoyl, acetyl, tert-butyl acetyl, para-phenylAttorney Docket No.206314-0002-WO01 benzoyl, and trifluoroacetyl. More preferred acyl groups include acetyl and benzoyl. The most preferred acyl group is acetyl.

[0027] The term “aromatic” or “aromatic group,” as used herein, means a monovalent group having a monocyclic ring structure or fused bicyclic ring structure. Monocyclic aromatic groups contain 5 to 10 carbon atoms, preferably 5 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring. Bicyclic aromatic groups contain 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in the ring. Aromatic groups are unsubstituted. The most preferred aromatic group is phenyl.

[0028] The term “carbocyclic” or “carbocyclic group,” as used herein, means a monovalent saturated or unsaturated hydrocarbon ring. Carbocyclic groups are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic carbocyclic groups contain 4 to 10 carbon atoms, preferably 4 to 7 carbon atoms, and more preferably 5 to 6 carbon atoms in the ring. Bicyclic carbocyclic groups contain 8 to 12 carbon atoms, preferably 9 to 10 carbon atoms in the ring. Carbocyclic groups are unsubstituted. Preferred carbocyclic groups include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. More preferred carbocyclic groups include cyclohexyl, cycloheptyl, and cyclooctyl. The most preferred carbocyclic group is cycloheptyl. Carbocyclic groups are not aromatic.

[0029] The term “FP receptor antagonist,” as used herein, means a compound or compounds that inhibit activation or function of one or more FP receptors. FP receptor antagonists further include prostaglandin analogs that act as prostaglandin antagonists, specifically, PGF antagonists. FP receptor antagonists selectively inhibit activation of the FP receptor and may not activate any other receptors that would negate the effect of inhibiting the FP receptor.

[0030] The term “fluoroalkyl,” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five, six, seven or eight hydrogen atoms are replaced by fluorine. Representative examples of fluoroalkyl include, but are not limited to, 2-fluoroethyl, 2,2,2- trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, and trifluoropropyl such as 3,3,3- trifluoropropyl.

[0031] The term “halogen,” “halogen atom,” or “halo,” as used herein, means Cl, Br, I, or F.

[0032] The term “halogenated hydrocarbon group,” as used herein, means a substituted monovalent hydrocarbon group or a substituted carbocyclic group, wherein at least one substituent is a halogen atom. Halogenated hydrocarbon groups can have a straight, branched, or cyclic structure. Preferred halogenated hydrocarbon groups have 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and most preferably 1 to 3 carbon atoms.Attorney Docket No.206314-0002-WO01 Preferred halogen atom substituents are Cl and F. The most preferred halogenated hydrocarbon group is trifluoromethyl.

[0033] The term “heteroaromatic group,” as used herein, means an aromatic ring containing carbon and 1 to 4 heteroatoms in the ring. Heteroaromatic groups are monocyclic or fused bicyclic rings. Monocyclic heteroaromatic groups contain 5 to 10 member atoms (i.e., carbon and heteroatoms), preferably 5 to 7, and more preferably 5 to 6 in the ring. Bicyclic heteroaromatic rings contain 8 to 12 member atoms, preferably 9 or 10 in the ring. Heteroaromatic groups are unsubstituted. Preferred heteroaromatic groups include thienyl, thiazolo, purinyl, pyrimidyl, pyridyl, and furanyl. More preferred heteroaromatic groups include thienyl, furanyl, and pyridyl. The most preferred heteroaromatic group is thienyl.

[0034] The term “heteroatom,” as used herein, means an atom other than carbon in the ring of a heterocyclic group or the chain of a heterogeneous group. Preferably, heteroatoms are selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Groups containing more than one heteroatom may contain different heteroatoms.

[0035] The term “heterocyclic group,” as used herein, means a saturated or unsaturated ring structure containing carbon and 1 to 4 heteroatoms in the ring. No two heteroatoms are adjacent in the ring. Heterocyclic groups are not aromatic. Heterocyclic groups are monocyclic, or are fused or bridged bicyclic ring systems. Monocyclic heterocyclic groups contain 4 to 10 member atoms (i.e., including both carbon atoms and at least 1 heteroatom), preferably 4 to 7, and more preferably 5 to 6 in the ring. Bicyclic heterocyclic groups contain 8 to 12 member atoms, preferably 9 or 10 in the ring. Heterocyclic groups are unsubstituted. Preferred heterocyclic groups include piperzyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and piperdyl.

[0036] The term “heterogeneous group,” as used herein, means a saturated or unsaturated chain containing 1 to 18 member atoms (i.e., including both carbon and at least one heteroatom). No two heteroatoms are adjacent. Preferably, the chain contains 1 to 12 member atoms, more preferably 1 to 6, and most preferably 1 to 4. The chain may be straight or branched. Preferred branched heterogeneous groups have one or two branches, preferably one branch. Preferred heterogeneous groups are saturated. Unsaturated heterogeneous groups have one or more double bonds, one or more triple bonds, or both. Preferred unsaturated heterogeneous groups have one or two double bonds or one triple bond. More preferably, the unsaturated heterogeneous group has one double bond. Heterogeneous groups are unsubstituted.

[0037] The term “lower monovalent hydrocarbon group,” as used herein, means a monovalent hydrocarbon group having 1 to 6, preferably 1 to 4 carbon atoms. “Lower alkyl” means a hydrocarbon chain of 1-4 carbon atoms.Attorney Docket No.206314-0002-WO01

[0038] The term “monovalent hydrocarbon group,” as used herein, means a chain of 1 to 18 carbon atoms, preferably 1 to 12, more preferably 1 to 6, and most preferably 1 to 4 carbon atoms. Monovalent hydrocarbon groups may have a straight chain or branched chain structure. Preferred monovalent hydrocarbon groups have one or two branches, preferably 1 branch. Preferred monovalent hydrocarbon groups are saturated. Unsaturated monovalent hydrocarbon groups have one or more double bonds, one or more triple bonds, or combinations thereof. Preferred unsaturated monovalent hydrocarbon groups have one or two double bonds or one triple bond; more preferred unsaturated monovalent hydrocarbon groups have one double bond.

[0039] The term “substituted aromatic group,” as used herein, means an aromatic group wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents. Preferred substituents include: halogen atoms, cyano groups, monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, heterogeneous groups, aromatic groups, substituted aromatic groups, or any combination thereof. More preferred substituents include halogen atoms, monovalent hydrocarbon groups, and substituted monovalent hydrocarbon groups. Preferred substituted aromatic groups include naphthyl. The substituents may be substituted at the ortho, meta, or para position on the ring, or any combination thereof. The preferred substitution pattern on the ring is ortho or meta. The most preferred substitution pattern is ortho.

[0040] The term “substituted carbocyclic group,” as used herein, means a carbocyclic group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents. Preferred substituents include: halogen atoms, cyano groups, monovalent hydrocarbon groups, monovalent heterogeneous groups, substituted monovalent hydrocarbon groups, aromatic groups, substituted aromatic groups, or any combination thereof. More preferred substituents include halogen atoms and substituted monovalent hydrocarbon groups. Carbocyclic group does not include aromatic rings.

[0041] The term “substituted heteroaromatic group,” as used herein, means a heteroaromatic group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents. Preferred substituents include: halogen atoms, cyano groups, monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, heterogeneous groups, substituted heterogeneous groups, phenyl groups, phenoxy groups, or any combination thereof. More preferred substituents include halogen atoms, halogenated hydrocarbon groups, monovalent hydrocarbon groups, and phenyl groups.

[0042] The term “substituted heterocyclic group,” as used herein, means a heterocyclic group wherein 1 to 4 hydrogen atoms bonded to carbon atoms in the ring have been replaced with other substituents. Preferred substituents include: halogen atoms, cyano groups,Attorney Docket No.206314-0002-WO01 monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, heterogeneous groups, substituted heterogeneous groups, halogenated hydrocarbon groups, phenyl groups, phenoxy groups, or any combination thereof. More preferred substituents include halogen atoms and halogenated hydrocarbon groups. Substituted heterocyclic groups are not aromatic.

[0043] The term “substituted heterogeneous group,” as used herein, means a heterogeneous group, wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms in the chain have been replaced with other substituents. Preferred substituents include halogen atoms, hydroxy groups, alkoxy groups (e.g., methoxy, ethoxy, propoxy, butoxy, and pentoxy), aryloxy groups (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, and acyloxyphenoxy), acyloxy groups (e.g., propionyloxy, benzoyloxy, and acetoxy), carbamoyloxy groups, carboxy groups, mercapto groups, alkylthio groups, acylthio groups, arylthio groups (e.g., phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, and alkyloxycarbonylphenylthio), aromatic groups (e.g., phenyl and tolyl), substituted aromatic groups (e.g., alkoxphenyl, alkoxycarbonylphenyl, and halophenyl), heterocyclic groups, heteroaromatic groups, and amino groups (e.g., amino, mono- and di- alkylamino having 1 to 3 carbon atoms, methylphenylamino, methylbenzylamino, alkanylamido groups of 1 to 3 carbon atoms, carbamamido, ureido, and guanidino).

[0044] The term “substituted monovalent hydrocarbon group,” as used herein, means a monovalent hydrocarbon group wherein 1 to 4 of the hydrogen atoms bonded to carbon atoms in the chain have been replaced with other substituents. Preferred substituents include halogen atoms; halogenated hydrocarbon groups; alkyl groups (e.g., methyl, ethyl, propyl, and butyl); hydroxy groups; alkoxy groups (e.g., methoxy, ethoxy, propoxy, butoxy, and pentoxy); aryloxy groups (e.g., phenoxy, chlorophenoxy, tolyloxy, methoxyphenoxy, benzyloxy, alkyloxycarbonylphenoxy, and acyloxyphenoxy); acyloxy groups (e.g., propionyloxy, benzoyloxy, and acetoxy); carbamoyloxy groups; carboxy groups; mercapto groups; alkylthio groups; acylthio groups; arylthio groups (e.g., phenylthio, chlorophenylthio, alkylphenylthio, alkoxyphenylthio, benzylthio, and alkyloxycarbonylphenylthio); aryl groups (e.g., phenyl, tolyl, alkoxyphenyl, alkoxycarbonylphenyl, and halophenyl); heterocyclyl groups; heteroaryl groups; and amino groups (e.g., amino, mono- and di- alkanylamino groups of 1 to 3 carbon atoms, methylphenylamino, methylbenzylamino, alkanylamido groups of 1 to 3 carbon atoms, carbamamido, ureido, and guanidino).

[0045] “Eflornithine” as used herein refers to a fluoroamino acid that is ornithine substituted by a difluoromethyl group at position 2. Eflornithine may also be referred to as 2- difluoromethyl-2,5-diaminopentanoic acid, 2-difluoromethyl-2,5-diaminovaleric acid, or Į- (difluoromethyl)ornithine. The abbreviation “DFMO” is employed to refer to Į- (difluoromethyl)ornithine.Attorney Docket No.206314-0002-WO01

[0046] “Pharmaceutically acceptable” means suitable for use in a human or other mammal.

[0047] The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloride, hydrobromide, sulfuric, phosphoric and the like.

[0048] “Safe and effective amount” means a quantity of a compound high enough to provide a significant positive modification of the subject’s condition or projected condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit / risk ratio).

[0049] As used herein, the terms “subject” and “patient” may be used interchangeably to refer to any vertebrate including, but not limited to, a mammal and a human. In some embodiments, the subject may be a human or a non-human. The subject or patient may be undergoing forms of treatment.

[0050] As used herein, the term “mammal” refers to any member of the class Mammalia including, without limitation, humans and nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats, llamas, camels, and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats, rabbits, guinea pigs, and the like. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be included within the scope of this term.

[0051] As used herein, the terms “treat,” “treating” or “treatment” are each used interchangeably to describe reversing, alleviating, or inhibiting the progress of a condition and / or injury, or one or more symptoms of such condition, to which such term applies. Depending on the condition of the subject, the term may also refer to preventing a condition,Attorney Docket No.206314-0002-WO01 and includes preventing the onset or severity of a condition, or preventing the symptoms associated with a condition. A treatment may be either performed in an acute or chronic way. The term also refers to reducing the severity of a disease or symptoms associated with such condition prior to affliction with the condition. Such prevention or reduction of the severity of a condition prior to affliction refers to administration of a pharmaceutical composition to a subject that is not at the time of administration afflicted with the condition. “Preventing” also refers to preventing the recurrence of a condition or of one or more symptoms associated with such condition. “Treatment” and “therapeutically,” refer to the act of treating, as “treating” is defined above. 2. Compounds

[0052] In one aspect, the disclosure relates to compounds for treating hair and skin conditions related to abnormal FPS units, wherein the hair and skin conditions may comprise PFB, AKN, HS, DCS, acne vulgaris, combinations thereof or the pigmentary changes related to them. In a particular embodiment, the compound may be a prostaglandin FP receptor antagonist (e.g., prostaglandin F receptor antagonist) or a selective modifier of the FP ligand to treat hair and skin conditions related to abnormal FPS units. The prostaglandin antagonist may interact strongly with hair-selective receptors, such as the FP receptor. The prostaglandin analog may selectively inhibit activation of the FP receptor and not activate any other receptors that would negate the effect of inhibiting the FP receptor. In another particular embodiment, the compound may be a polyamine pathway inhibitor, an ornithine decarboxylase inhibitor, or polyamine such as any of the compounds as disclosed in U.S. Patent No.7,374,770; U.S. Patent No.8,551,462; U.S. Patent No.7,432,302; U.S. Patent No.5,811,634; U.S. Patent No. 5,132,293; U.S. Patent No.6,743,822; U.S. Patent No.7,015,349; U.S. Patent No.7,261,878; U.S. Patent No.5,132,293; U.S. Patent No.4,720,489; U.S. Patent No.5,648,394; U.S. Patent No.7,314,959; U.S. Patent No.7,045,550; U.S. Patent Application Publication No. 2004 / 0131574; U.S. Patent Application Publication No.2004 / 0006045; U.S. Patent Application Publication No.2003 / 0036561; U.S. Patent Application Publication No.2003 / 0199584; U.S. Patent Application Publication No.2003 / 0185778; International Patent Application Publication No.2009 / 052518; International Patent Application Publication No.2014 / 080015; and International Patent Application Publication No.2005 / 105729, each of which is incorporated herein by reference in their entireties.

[0053] In another embodiment, the compound may be an ornithine decarboxylase inhibitor. The ornithine decarboxylase inhibitor may be 2-(difluoromethyl)-2,5-diaminopentanoic acid; alpha-ethynyl ornithine; 6-heptyne-2,5-diamine; or 2-methyl-6-heptyne diamine. In an embodiment, the ornithine decarboxylase inhibitor may be eflornithine, in particular eflornithine hydrochloride. Eflornithine, and salts thereof, corresponding methods of synthesis, andAttorney Docket No.206314-0002-WO01 methods of testing activity are described in U.S. Patent No.4,413,141, which is incorporated herein by reference in its entirety. Eflornithine hydrochloride also known as VANIQA®is (±)-2- (difluoromethyl) ornithine monohydrochloride monohydrate, with the empirical formula C6H12F2N2O2xHCl xH2O, a molecular weight of 236.65 and the following structural formula, formula (I):

[0054] VANIQA®is described by U.S. Patent No.5,648,394 and U.S. Patent No.4,720,489, each of which is incorporated herein by reference in their entireties. Anhydrous eflornithine hydrochloride has an empirical formula C6H12F2N2O2xHCl and a molecular weight of 218.65. Other ingredients included in VANIQA®may be ceteareth-20, cetearyl alcohol, dimethicone, glyceryl stearate, methylparaben, mineral oil, PEG-100 stearate, phenoxyethanol, propylparaben, stearyl alcohol, and water. Eflornithine hydrochloride irreversibly inhibits in skin the activity of the enzyme ornithine decarboxylase (ODC). ODC is necessary in the synthesis of polyamines.

[0055] Additional suitable compounds that may be used for treating hair and skin conditions related to abnormal FPS units may include the following: prostaglandin F2a (FP) receptor antagonists (US10159634B2, US2007 / 0004620A1, US10259795B2, US11149018B2; such as OBE002 ([(S)-3-(biphenyl-4-sulfonyl)-thiazolidine-2-carboxylic acid [(S)-1-(4-fluoro-phenyl)-3- hydroxy-propyl]-amide]), OBE022 ([(S)-2-amino-3-methyl-butyric acid (S)-3-{[(S)-3-(biphenyl-4- sulfonyl)-thiazolidine-2-carbonyl]-amino}-3-(4-fluoro-phenyl)-propyl ester]), and BAY-6672 ((4R)-5-[(6-bromo-3-methyl-2-pyrrolidin-1-ylquinoline-4-carbonyl)amino]-4-(2- chlorophenyl)pentanoic acid)); a prostaglandin D2 receptor, DP-2 agonist (WO2013142295A1); prostaglandin synthetase inhibitors; a Wnt inhibitor (US20120165270A1); advanced glycation end products (AGE’s) and compounds such as lysine (WO2010063678A2, WO2010063673A2); extracts of tetraselmis species (US20100143267A1); fibroblast growth factor (FGF)18 (WO2008102782A1); FGF5 (US20160009797A1); cytotoxic lectin (US20080145330A1); trypsin and other enzymes (US20070269418A1); extract of Juniperus genus and / or malt extract (US6375948 and US7211278); hair growth-inhibiting active substances (WO06125582A1); extract of ginger root (US20060099280A1); toxalbumins such as ricin, abrin, or modeccin and the like (US20060034952A1); inhibitors of cysteine pathway enzymes (WO9524885A1);Attorney Docket No.206314-0002-WO01 inhibitors of nitric oxide synthetase (WO9524884A1); ornithine amino transferase inhibitors (WO9524181A1); cyclooxygenase inhibitors such as NSAIDs (WO9427586A1); 5-lipoxygenase inhibitors (WO9427563A1) substances such as substituted guanidines or amidines (WO8808295A1); heparanase inhibitors or antisense oligonucleotides targeted to heparanase (WO2004006949A1); nicotinamide (WO2016102969A1); inhibitor of phosphofructokinase (US5824665); DNA polymerase inhibitor (US20100137341A1); heat shock protein inhibitor (US20090182031A1); methyl palmoxirate (US7160921); nordihydroguaiaretic acid (US6414017); NK1 receptor antagonists; platelet activating factor receptor antagonists (US6093748); and aminobenzophenones (US3426137). Other suitable compounds that may be used for treating hair and skin conditions related to abnormal FPS units as described herein may include compounds disclosed and described in one or more of the following references: WO2011014649A1, WO2022125876A1, US9655833, US9707169B2, US10159634B2, US20120245205A1, US20190314259A1, US20210220248A1, US63 / 331,500, US63 / 496,581, and US63 / 409,563. Each of the foregoing references is incorporated herein by reference in their entireties.

[0056] The FP receptor antagonist may be a compound of formula (II), or a pharmaceutically acceptable salt thereof, ,

[0057] wherein G, R1, R2, R4, and n are as described below.

[0058] G may

[0059] R1may be tert-butyl or phenyl, wherein the phenyl is optionally substituted with 1-3 R1a;Attorney Docket No.206314-0002-WO01

[0060] R1a, at each occurrence, may be independently C1-4alkyl, C1-4fluoroalkyl, halogen, cyano, –OC1-4alkyl, or –OC1-4fluoroalkyl;

[0061] R2may be –C1-4alkyl, or –C1-4alkylene–OC(O)CH

[0062] R2amay be hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl, –C1-4alkylene–C3-6cycloalkyl, –C1-4alkylene–OH, or –C1-4alkylene–OC1-4alkyl;

[0063] R3, at each occurrence, may be independently C1-4alkyl, C1-4fluoroalkyl, halogen, cyano, –OC1-4alkyl, or –OC1-4fluoroalkyl;

[0064] R4, at each occurrence, may be independently C1-4alkyl or C1-4fluoroalkyl;

[0065] m may be 0, 1, 2, 3, 4, or 5; and

[0066] n may be 0, 1, 2, 3, or 4.

[0067] In an embodiment, R1may be phenyl.

[0068] In an embodiment, R2may be –C1-4alkylene–OH.

[0069] In an embodiment, R2may be –CH2CH2OH.

[0070] In an embodiment, R2may be –C1-4alkylene–OC(O)CH(NH2)R2a, such as (S)–C1-4alkylene–OC(O)CH(NH2)R2aor (S)–C1-4alkylene–OC(O)CH(NH2)R2a. Preferably, –C1-4alkylene–OC(O)CH(NH2)R2amay be (S)–C1-4alkylene–OC(O)CH(NH2)R2a. R2may be – CH2CH2–OC(O)CH(NH2)R2a, such as (S)–CH2CH2–OC(O)CH(NH2)R2aor (R)–CH2CH2– OC(O)CH(NH2)R2a. Preferably, –CH2CH2–OC(O)CH(NH2)R2amay be (S)–CH2CH2– OC(O)CH(NH2)R2a. R2may be –C1-4alkylene–OC(O)CH(NH2)CH(CH3)2, such as (S)–C1-4alkylene–OC(O)CH(NH2)CH(CH3)2or (R)–C1-4alkylene–OC(O)CH(NH2)CH(CH3)2. Preferably, –C1-4alkylene–OC(O)CH(NH2)CH(CH3)2may be (S)–C1-4alkylene–OC(O)CH(NH2)CH(CH3)2. R2may be –CH2CH2–OC(O)CH(NH2)CH(CH3)2, such as (S)–CH2CH2–OC(O)CH(NH2)CH(CH3)2 or (R)–CH2CH2–OC(O)CH(NH2)CH(CH3)2. Preferably, –CH2CH2–OC(O)CH(NH2)CH(CH3)2may be (S)–CH2CH2–OC(O)CH(NH2)CH(CH3)2. Preferred pharmaceutically acceptable salts of the primary amino group include the hydrochloride, mesylate, hydrosulfate, sulfate, dihydrophosphate, citrate, edisylate, and fumarate.

[0071] In an embodiment, R3may be fluoro, chloro, CH3, or OCH3; and m may be 0, 1, or 2.Attorney Docket No.206314-0002-WO01Attorney Docket No.206314-0002-WO01

[0074] In an embodiment, n may be 0.

[0075] The compound of formula (II) may have formula (II-A) .Attorney Docket No.206314-0002-WO01

[0077] The compounds of formula (II), and salts thereof, corresponding methods of synthesis, and methods of testing for FP receptor antagonist activity are described in U.S. patent nos.8,415,480, 9,447,055, 9,834,528, and 10,259,795 which are incorporated herein by reference.

[0078] The FP receptor antagonist may be a compound of formula (III), or a pharmaceutically acceptable salt thereof,

[0079] wherein R10, R20, R30, R40, R50, R60, R70A, R70B, R80, R90, and Ar are as described below.

[0080] Ar may be phenyl or pyridinyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents, the pyridinyl is unsubstituted or substituted with 1-2 substituents, and the substituents are independently selected from the group consisting of fluoro, chloro, C1-4alkyl, C3-4cycloalkyl, –OC1-2alkyl, –SC1-2alkyl, C1-4alkyl substituted by 1-3 fluoro, C3-4cycloalkyl substituted by 1-4 fluoro, –OC1-2alkyl substituted by 1-3 fluoro, –SC1-2alkyl substituted by 1-3 fluoro, or where two substituents of the phenyl or pyridinyl on adjacent ring atoms together form a methylenedioxy or ethylenedioxy;

[0081] L may be a bond or –X–(CRaRb)k–;

[0082] X may be a bond, CH2, O, S, S(O), S(O)2, or N(R);

[0083] R may be hydrogen or CH3;

[0084] Raand Rbmay be independently hydrogen, fluoro, or CH3; or Raand Rbtogether with the carbon atom to which they attach form a cyclopropyl;

[0085] k may be 1, 2, 3, or 4;

[0086] R10may be halogen, C1-4alkyl, C1-4alkyl substituted by 1-5 fluoro, –OCH3, –OCH2F, – OCHF2, –OCF3, –SCF3, –SF5, –SiCH3, ethynyl, cyclopropyl, or cyclobutyl, where the cyclopropyl and cyclobutyl are unsubstituted or substituted by 1-4 fluoro;Attorney Docket No.206314-0002-WO01

[0087] R20, R30, and R40may be independently hydrogen, halogen, CH3, CH2F, CHF2, or CF3;

[0088] R50may be halogen, C1-4alkyl, C1-4alkyl substituted by 1-5 fluoro, –OCH3, –OCH2F, – OCHF2, –OCF3, OH, –SCH3, –SCF3, cyano, ethenyl, cyclopropyl, or cyclobutyl, where the cyclopropyl and cyclobutyl are unsubstituted or substituted by 1-4 fluoro;

[0089] R60may be –NRcRd;

[0090] Rcmay be hydrogen or C1-3alkyl;

[0091] Rdmay be C1-4alkyl, C3-7cycloalkyl, C1-4alkyl substituted by 1-5 fluoro, C1-4alkyl monosubstituted by C3-6cycloalkyl, –OCH3, –OCF3, or phenyl, wherein the C3-7cycloalkyl is optionally substituted with 1-4 fluoro; or

[0092] Rcand Rdtogether with the nitrogen to which they attach may form a saturated or partially unsaturated 4- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocyclic ring, the heterocyclic rings optionally containing a ring member selected from the group consisting of O, N, S, SO, and S(O)2, wherein the heterocyclic rings may be optionally substituted with 1-4 substituents independently selected from the group consisting of fluoro, C1-4alkyl, OH, oxo, –OC1-3alkyl, –OCHF2, –OCF3, cyano, NH2, NHCH3, N(CH3)2, C(O)NH2, C(O)NHCH3, C(O)N(CH3)2, C1-4alkyl substituted with 1-5 fluoro, and C1-4alkyl monosubstituted with OH or –OCH3;

[0093] R70Aand R70Bmay be independently hydrogen or CH3, or R70Aand R70Btogether with the carbon atom to which they attach form a cyclopropyl;

[0094] R80may be hydrogen, fluoro, CH3, CF3, CH2CH3, or OH; and

[0095] R90may be hydrogen or CH3.

[0096] In an embodiment, Ar may be phenyl, wherein the phenyl may be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of fluoro, chloro, CH3, CF3, OCH3, OCHF2, and OCF3;

[0097] In an embodiment, L may be –CH2CH2–;

[0098] In an embodiment, R10may be bromo;

[0099] In an embodiment, R50may be CH3;Attorney Docket No.206314-0002-WO01

[0101] In an embodiment, R14may be fluoro or CH3; and

[0102] In an embodiment, R15may be fluoro, CH3, or CH2CH3.

[0103] The compound of formula (III) may be

[0104] The compounds of formula (III), and salts thereof, corresponding methods of synthesis, and methods of testing for FP receptor antagonist activity are described in US2020 / 0157073, which is incorporated herein by reference.

[0105] Additional suitable compounds that may be used for treating hair and skin conditions related to abnormal FPS units may include a PGF analog having the structure of general formula (IV):Attorney Docket No.206314-0002-WO01 or structure according to general formula (V):

[0106] wherein R is selected from the group consisting of CO2H, C(O)NHOH, CO2R1, CH2OH, S(O)2R1, C(O)NHR1, P(O)(OR1) R2, C(O)NHS(O)2R1, and tetrazole. R1and R2are independently selected from the group consisting of a hydrogen atom or a monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, aromatic groups, substituted aromatic groups, carbocyclic groups, substituted carbocyclic groups, heterogeneous groups, substituted heterogeneous groups, heterocyclic groups, substituted heterocyclic groups, heteroaromatic groups, and substituted heteroaromatic groups. Preferably, R1and R2are selected from the group consisting of CH3, C2H5, and C3H7. Preferably, R is selected from the group consisting of CO2H, CO2CH3, C(O)NHC2H5, CO2C2H5, CO2C3H7, CO2C4H9, CO2C3H7O2, and C(O)NHS(O)2R1. More preferably, R is selected from the group consisting of CO2H, CO2CH3, CO2C2H5, C(O)NHC2H5and CO2C3H7. Most preferably, R is selected from the group consisting of CO2H, CO2CH3, C(O)NHC2H5and CO2C3H7.

[0107] W is -CH2-, -O-, or -S(O)2-. In certain embodiments, W is -CH2-.

[0108] X is halogen, lower alkyl, alkoxy, or hydrogen. In certain embodiments, X is methoxy or methyl. In certain embodiments, X is F.

[0109] An example of compounds according to general formula (IV) or (V) may include 11- deoxy-16-fluoro PGF2αanalogs such as AL-3138.

[0110] PGF analogs may be synthesized by methods known by one of skill in the art. PGF analogs may be purchased commercially, for example, from Cayman Chemicals (Ann Arbor, MI).

[0111] Examples of compounds according to formula (IV) or (V) may include the following:Attorney Docket No.206314-0002-WO01.

[0112] In other embodiments, compounds useful in the methods according to the invention may be of general formula (VI):Attorney Docket No.206314-0002-WO01

[0113] wherein G is selected from the group consisting of substituted or unsubstituted C1- C6-a1kyl aryl, substituted or unsubstituted C1-C6-alkyl heteroaryl, substituted or unsubstituted C1-C6-alkyl cycloalkyl, substituted or unsubstituted C1-C6-alkyl heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8- cycloalkyl or -heterocycloalkyl, said cycloalkyl or aryl or heteroaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups;

[0114] R1is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (hetero)- cycloalkyl or aryl or heteroaryl groups;

[0115] R2is H, carboxy, acyl, alkoxycarbonyl, aminocarbonyl, substituted or unsubstituted C1-C5-alkyl carboxy, substituted or unsubstituted C1-C5-alkyl acyl, substituted or unsubstituted C1-C5-alkyl alkoxycarbonyl, substituted or unsubstituted C1-C5-alkyl aminocarbonyl, substituted or unsubstituted C1-C5-alkyl acyloxy, substituted or unsubstituted C1-C5-alkyl acylamino, substituted or unsubstituted C1-C5-alkyl ureido, substituted or unsubstituted C1-C5-alkyl amino, substituted or unsubstituted C1-C5-alkyl alkoxy, substituted or unsubstituted C1-C5-alkyl sulfanyl, substituted or unsubstituted C1-C5-alkyl sulfinyl, substituted or un substituted C1-C5-alkyl sulfonyl, substituted or unsubstituted C1-C5-alkyl sulfonylamino, substituted or unsubstituted C1- C5-alkyl sulfonyloxy, substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C1-C6-a1kyl aryl, substituted or unsubstituted C2-C6-alkyl heteroaryl, substituted or unsubstituted C1-C6-alkyl cycloalkyl, substituted or unsubstituted C1-C6-alkyl heterocycloalkyl, substituted or unsubstituted C2-C6-alkenyl aryl, substituted or unsubstituted C2-C6-alkenyl heteroaryl, substituted or unsubstituted C2-C6-alkynyl aryl, or substituted or unsubstituted C2-C6-a1kynyl heteroaryl; alternatively, R2and G may form a C3-C8-cycloalkyl ring;Attorney Docket No.206314-0002-WO01 R4is selected from the group consisting of substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl; and n is an integer from 0 to 2.

[0116] According to some embodiments, G is an aryl group, e.g., a substituted or unsubstituted phenyl, like a biphenyl.

[0117] An example of a compound according to general formula (VI) may include that of AS604872:

[0118] In other embodiments, compounds useful in methods of inhibiting the activation of the FP receptor according to the invention may include compounds, peptides, and peptidomimetics disclosed in U.S. Patent No.7,521,530, which is incorporated herein by reference in its entirety. Compounds useful in the methods according to the invention may be of general formula (VII): Y-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-Z (VII) wherein Y is attached to the amino-terminus of said peptide and is selected from the group consisting of a hydrogen atom, an acetyl group, a benzoyl group, an acyl group (R--CO--), wherein R is a hydrophobic moiety, or an aroyl group (Ar--CO--), wherein Ar is an aryl group; AA1and AA2are independently selected from the group consisting of no residue, isoleucine (Ile), leucine (Leu), and related alpha-amino acids possessing hydrophobic side-chains; AA3is selected from the group consisting of no residue, glycine (Gly), alanine (Ala), and proline (Pro);Attorney Docket No.206314-0002-WO01 AA4is selected from the group consisting of histidine (His), phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), and related alpha-amino acids possessing hydrophobic side-chains; AA5is selected from the group consisting of arginine (Arg), ornithine (Orn), lysine (Lys), citruline, 2-, 3-, and 4-pyridylalanine, and arginine surrogates; AA6is selected from the group consisting of aspartic acid (Asp), asparagine (Asn), glutamic acid (Glu), glutamine (Gln), serine (Ser), 3-amino-5-phenylpentanoic acid, and Phe; AA7is selected from the group consisting of no residue, Tyr, Phe, and related alpha-amino acids possessing hydrophobic side-chains, aromatic and arylalkyl amines, and aliphatic amines; AA8is selected from the group consisting of no residue, Lys, Leu, Tyr, alpha-amino acids possessing hydrophobic side-chains, and aromatic and aliphatic amines; and Z is attached to the carboxy-terminus of said peptide and is selected from the group consisting of, a hydroxyl group, NH2, and aromatic and aliphatic amines; and functional derivatives thereof.

[0119] An example of a compound according to general formula (VII) is Ile-Leu-Gly-His- (citrulline)-Asp-Tyr-Lys (SEQ ID NO: 1), also known as THG113.31.

[0120] In other embodiments, compounds useful in the methods according to the invention may be of general formula (VIII): Y-BTM-AA1-AA2-AA3-Z (VIII) wherein Y is attached to the amino-terminus of the peptide and is selected from the group consisting of a hydrogen atom, an acyl group (R--CO--), wherein R is a hydrophobic moiety, or an aroyl group (Ar--CO--), wherein Ar is an aryl group; BTM (beta turn mimetic) is a dipeptide surrogate; AA1is selected from the group consisting of Arg, Orn, Lys, citruline, 2-, 3-, and 4-pyridylalanine, and arginine surrogates; AA2 is selected from the group consisting of Asp, Asn, Glu, Gln, Ser, 3-amino-5- phenylpentanoic acid and Phe; AA3is selected from the group consisting of no residue, Tyr, Phe, and related alpha-amino acids possessing hydrophobic side-chains, and aromatic amines, aliphatic amines and primary arylalkyl amines; and Z is selected from the group consisting of no residue, a hydroxyl group, NH2, and aromatic, heteroaromatic and aliphatic amines; and functional derivatives thereof.Attorney Docket No.206314-0002-WO01

[0121] Compounds such as ((2S)-3-((1,1'-biphenyl)-4-ylsulfonyl)-N-((R)-phenyl(2- pyridinyl)methyl)-1,3-thiazolidine-2-carboxamide) are found in US Patent Application US 2008 / 0255094 A1 and International Patent Application WO 03 / 082278 A1, each of which is incorporated herein by reference in their entireties, and are specifically contemplated for use in the compositions and methods of the present invention. Compounds such as 11β-fluoro-15β- hydroxy PGF2α analogs, such as those disclosed in US Patent No.6,649,655, which is incorporated by reference herein in its entirety, are also useful and contemplated. In addition, peptides that inhibit FP activation by a different mechanism, such as those found in US Patent Application Publication No. US 2006 / 0211626 A1, are also useful and specifically contemplated, and pharmaceutically acceptable salts, hydrates, and biohydrolyzable amides, esters, and imides thereof are also suitable.

[0122] Optical isomers, diastereomers, and enantiomers of the structures described above are also suitable compounds of this invention. At all stereocenters where stereochemistry is not defined (i.e., C11, C12, C15, and C16), both epimers are envisioned. 3. Pharmaceutical Compositions

[0123] A compound as described herein may be incorporated into pharmaceutical compositions suitable for administration to a subject, such as a patient. The pharmaceutical composition may be prepared for administration to a subject. Such pharmaceutical compositions can be administered in dosages and by techniques well known to those skilled in the medical and pharmaceutical arts taking into consideration such factors as the age, sex, weight, and condition of the particular subject, and the route of administration. The compositions may be for topical or oral administration. In an embodiment, a topical composition may be prepared by methods as described in U.S. Patent No.5,648,394.

[0124] A compound as described herein is an active ingredient formulated into a composition, such as a pharmaceutical or cosmetic composition, administered for treatment or prophylaxis of a condition, including, for example, hair and skin conditions related to abnormal FPS units including PFB, AKN, HS, DCS, acne vulgaris, and combinations thereof. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. (1990).

[0125] The composition may further comprise a carrier. “Carrier” means one or more compatible substances that are suitable for administration to a mammal. Carrier includes solid or liquid fillers, diluents, hydrotopes, surface-active agents, and encapsulating substances. “Compatible” means that the components of the composition are capable of being commingled with a compound as described herein, and with each other, in a manner such that there is no interaction which would substantially reduce the efficacy of the composition under ordinary useAttorney Docket No.206314-0002-WO01 situations. Carriers must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the mammal being treated. The carrier can be inert, or it can possess pharmaceutical benefits, cosmetic benefits, or both.

[0126] The choice of carrier depends on the route by which a compound as described herein will be administered and the form of the composition. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, or parenteral) or topical administration (e.g., local application on the skin, ocular, liposome delivery systems, or iontophoresis). Topical and / or oral administration is preferred.

[0127] Carriers for systemic administration typically comprise one or more ingredients selected from the group consisting of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others.

[0128] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; polyols such as propylene glycol; calcium carbonate; sodium carbonate; cellulose; glycerin; mannitol; and sorbitol.

[0129] Suitable lubricants are exemplified by solid lubricants including silica, talc, stearic acid and its magnesium salts and calcium salts, calcium sulfate; and liquid lubricants such as polyethylene glycol and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma.

[0130] Suitable binders include polyvinylpyrilidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, and sodium carboxymethylcellulose.

[0131] Suitable disintegrants include starches, agar, alginic acid and the sodium salt thereof, effervescent mixtures, and croscarmelose.

[0132] A colorant may be an FD&C dye.

[0133] A flavor may be menthol, peppermint, and / or fruit flavors.

[0134] A sweetener may be aspartame and / or saccharin.

[0135] An antioxidant may be BHA, BHT, and / or vitamin E.

[0136] A preservative may be methyl paraben and / or sodium benzoate.

[0137] A glidant may be silicon dioxide.Attorney Docket No.206314-0002-WO01

[0138] A solvent may be water, isotonic saline, ethyl oleate, alcohols such as ethanol, and / or phosphate buffer solutions.

[0139] Suitable suspending agents include cellulose and its derivatives, such as methyl cellulose and sodium carboxymethyl cellulose; Avicel® RC-591 from FMC Corporation of Philadelphia, Pennsylvania; tragacanth and sodium alginate.

[0140] A wetting agent may be lecithin, polysorbate 80, and / or sodium lauryl sulfate.

[0141] A surfactant may be the TWEENS® from Atlas Powder Company of Wilmington, Delaware.

[0142] Compositions for parenteral administration typically comprise 0.1 to 10% of a compound as described herein and 90 to 99.9% of a carrier comprising a diluent, a lubricant, a binder, and a solvent.

[0143] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms comprise a safe and effective amount, usually at least 5%, and preferably from 25% to 50%, of a compound as described herein. The oral dosage compositions further comprise 50 to 95% of a carrier, preferably 50 to 75%.

[0144] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film- coated, or multiple-compressed. Tablets typically comprise a compound as described herein, and a carrier comprising ingredients selected from the group consisting of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, and combinations thereof. Preferred diluents include calcium carbonate, sodium carbonate, mannitol, lactose and cellulose. Preferred binders include starch, gelatin, and sucrose. Preferred disintegrants include starch, alginic acid, and croscarmellose. Preferred lubricants include magnesium stearate, stearic acid, and talc. Preferred colorants are the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, and fruit flavors.

[0145] Capsules (including time release and sustained release formulations) typically comprise a compound as described herein, and a carrier comprising one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a compound as described herein, and preferably further comprise glidants such as silicon dioxide to improve flow characteristics.

[0146] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability. One skilled in the art would know how to select appropriate ingredients without undue experimentation.Attorney Docket No.206314-0002-WO01

[0147] The solid compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that a compound as described herein is released in the gastrointestinal tract in the vicinity of the desired application, or at various times to extend the desired action. The coatings typically comprise one or more components selected from the group consisting of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT® coatings (available from Rohm & Haas G.M.B.H. of Darmstadt, Germany), waxes and shellac.

[0148] Compositions for oral administration can also have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically comprise a compound as described herein and a carrier comprising ingredients selected from the group consisting of: diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably comprise one or more ingredients selected from the group consisting of colorants, flavors, and sweeteners.

[0149] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose. Such compositions may further comprise lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0150] The compositions may further comprise an optional activity enhancer. The activity enhancers are exemplified by compounds that work marginally, if at all by itself, but can help the activity of the compounds as described herein.

[0151] A penetration enhancer can be added to all of the compositions for systemic administration except compositions for oral administration. The amount of penetration enhancer, when present in the composition, may typically be 1% to 5%. Examples of penetration enhancers include 2-methyl propan-2-ol, propan-2-ol, ethyl-2-hydroxypropanoate, hexan-2,5-diol, POE(2) ethyl ether, di(2-hydroxypropyl) ether, pentan-2,4-diol, acetone, POE(2) methyl ether, 2-hydroxypropionic acid, 2-hydroxyoctanoic acid, propan-1-ol, 1,4-dioxane, tetrahydrofuran, butan-1,4-diol, propylene glycol dipelargonate, polyoxypropylene 15 stearyl ether, octyl alcohol, POE ester of oleyl alcohol, oleyl alcohol, lauryl alcohol, dioctyl adipate, dicapryl adipate, di-isopropyl adipate, di-isopropyl sebacate, dibutyl sebacate, diethyl sebacate, dimethyl sebacate, dioctyl sebacate, dibutyl suberate, dioctyl azelate, dibenzyl sebacate, dibutyl phthalate, dibutyl azelate, ethyl myristate, dimethyl azelate, butyl myristate, dibutyl succinate,Attorney Docket No.206314-0002-WO01 didecyl phthalate, decyl oleate, ethyl caproate, ethyl salicylate, iso-propyl palmitate, ethyl laurate, 2-ethyl-hexyl pelargonate, iso-propyl isostearate, butyl laurate, benzyl benzoate, butyl benzoate, hexyl laurate, ethyl caprate, ethyl caprylate, butyl stearate, benzyl salicylate, 2- hydroxypropanoic acid, 2-hyroxyoctanoic acid, dimethyl sulphoxide, N,N-dimethyl acetamide, N,N-dimethyl formamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, 5-methyl-2-pyrrolidone, 1,5- dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, phosphine oxides, sugar esters, tetrahydrofurfural alcohol, urea, diethyl-m-toluamide, 1-dodecylazacyloheptan-2-one, and combinations thereof.

[0152] In certain embodiments, the compounds as described herein are topically administered. Topical compositions that can be applied locally to the skin may be in any form including intralesional injections, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, mousses, sprays, foam, skin patches, and the like. The compound or composition may be administered to a subject with an agent that increases absorption of the compound such as a low-level laser or microneedling. Topical compositions may comprise: a compound as described herein and a carrier. The carrier of the topical composition may aid penetration of the compounds as described herein into the skin to reach the environment where the compounds are needed. The carrier may further comprise one or more optional components described above.

[0153] The exact amounts of each component in the topical composition depend on various factors. The amount of the compound depends on the binding affinity (IC50) of the compound selected. The amount of the compound added to the topical composition is: IC50x 10-1≥ % of a compound described herein ≥ IC50x 10-5, where IC50is expressed in nanomolar. For example, if the binding affinity of the compound is 1 nM, the amount of the compound will be 0.00001 to 0.1%. If the binding affinity of the compound is 10 nM, the amount of the compound will be 0.0001 to 0.1%. In certain embodiments, the amount of the compound in the topical composition may be from 0.0001 to 25%, from 0.0001 to 20%, from 0.0001 to 10%, from 0.0001 to 1%, from 0.0001 to 0.1%, from 0.001 to 25%, from 0.001 to 20%, from 0.001 to 10%, from 0.001 to 1%, from 0.001 to 0.1%, from 0.01 to 25%, from 0.01 to 20%, from 0.01 to 10%, from 0.01 to 1%, from 0.01 to 0.1%, from 0.1 to 25%, from 0.1 to 20%, from 0.1 to 10%, from 0.1 to 1%, from 1 to 10%, from 1 to 20%, from 1 to 25%, from 10 to 20%, from 10 to 25%, or from 20 to 25%, based on the IC50and skin penetration behavior of the compound. In certain preferred embodiments, the amount of the compound in the topical composition is from 1 to 10%. The amount and dosage of a compound as described herein are critical. If the amount of the compound is outside the ranges specified above (i.e., either higher or lower), efficacy of the treatment will be reduced.

[0154] The carrier may comprise a single component or a combination of two or more components. Typical carriers in the topical compositions may include water, alcohols, aloe veraAttorney Docket No.206314-0002-WO01 gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, combinations thereof, and the like. Preferred carriers include alcohols, mineral oil, and water.

[0155] The carrier of the topical composition may further comprise one or more ingredients selected from the group consisting of emollients, propellants, solvents, humectants, thickeners, powders, and fragrances.

[0156] The amount of an emollient in the topical composition may be 5 to 95%. Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, glyceryl monostearate, propane- 1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate, stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, polydimethylsiloxane, di-n-butyl sebacate, iso- propyl myristate, iso-propyl palmitate, iso-propyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Preferred emollients include stearyl alcohol and polydimethylsiloxane.

[0157] The amount of a propellant in the topical composition may be 5 to 95%. Suitable propellants include propane, butane, iso-butane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof.

[0158] The amount of a solvent in the topical composition may be 5 to 95%. Suitable solvents include water, ethyl alcohol, methylene chloride, iso-propanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Preferred solvents include ethyl alcohol.

[0159] The amount of a humectant in the topical composition may be 5 to 95%. Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Preferred humectants include glycerin.

[0160] The amount of a thickener in the topical composition may be 0 to 95%.

[0161] The amount of a powder in the topical composition may be 0 to 95%. Suitable powders include chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof.Attorney Docket No.206314-0002-WO01

[0162] The amount of a fragrance in the topical composition may be 0.001 to 0.5%, preferably 0.001 to 0.1%.

[0163] Any activity enhancers may be added to the topical compositions. In certain embodiments, the topical composition may comprise 0.01 to 15% of at least one of the activity enhancers. More preferably, the composition comprises 0.1 to 10%, and most preferably 0.5 to 5% of at least one of the activity enhancers. In certain embodiments, the topical composition comprises 1 to 5% of an activity enhancer.

[0164] In certain embodiments, pharmaceutical compositions may further comprise additional active agents including, but not limited to, sunscreens and sunblocks, anti- oxidants / radical scavengers, topical steroids, and retinoids.

[0165] In an alternative embodiment of the invention, pharmaceutical compositions for topical administration are prepared by conventional methods. Pharmaceutical compositions for topical administration typically comprise a compound as described herein, a carrier, such as purified water, and one or more ingredients selected from the group consisting of sugars such as dextrans, particularly dextran 70, cellulose or a derivative thereof, a salt, disodium EDTA (Edetate disodium), and a pH adjusting additive.

[0166] Examples of cellulose derivatives suitable for use in the pharmaceutical composition for topical administration include sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and hydroxypropylmethylcellulose. Hydroxypropylmethylcellulose is preferred.

[0167] Examples of salts suitable for use in the pharmaceutical compositions for topical administration include sodium chloride, potassium chloride, and combinations thereof.

[0168] Examples of pH adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of the pharmaceutical composition for topical administration to 3.5-8.0.

[0169] The compounds as described herein may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines. A preferred formulation for topical delivery of the present compounds uses liposomes as described in Dowton et al., “Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin”, S.T.P. Pharma Sciences, Vol.3, pp.404 - 407 (1993); Wallach and Philippot, “New Type of Lipid Vesicle: Novasome®”, Liposome Technology, Vol.1, pp.141 - 156 (1993); Wallach, U.S. Patent No.4,911,928, assigned to Micro-Pak, Inc., issued March 27, 1990; and Weiner et al., U.S. Patent No.5,834,014, assigned to The University of Michigan and Micro-Pak, Inc., issued November 10, 1998 (with respect to Weiner et al., with a compound as described herein administered in lieu of, or in addition to, minoxidil).Attorney Docket No.206314-0002-WO01

[0170] The compounds as described herein may also be administered by iontophoresis. See, e.g., internet site www.unipr.it / arpa / dipfarm / erasmus / erasm14.html; Banga et al., “Hydrogel-based Iontotherapeutic Delivery Devices for Transdermal Delivery of Peptide / Protein Drugs”, Pharm. Res., Vol.10 (5), pp.697-702 (1993); Ferry, “Theoretical Model of Iontophoresis Utilized in Transdermal Drug Delivery”, Pharmaceutical Acta Helvetiae, Vol 70, pp.279-287 (1995); Gangarosa et al., “Modern Iontophoresis for Local Drug Delivery”, Int. J. Pharm, Vol.123, pp.159-171 (1995); Green et al., “Iontophoretic Delivery of a Series of Tripeptides Across the Skin in vitro”, Pharm. Res., Vol 8, pp.1121-1127 (1991); Jadoul et al., “Quantification and Localization of Fentanyl and TRH Delivered by Iontophoresis in the Skin”, Int. J. Pharm., Vol.120, pp.221-8 (1995); O'Brien et al., “An Updated Review of its Antiviral Activity, Pharmacokinetic Properties and Therapeutic Efficacy”, Drugs, Vol.37, pp.233-309 (1989); Parry et al., “Acyclovir Bioavailability in Human Skin”, J. Invest. Dermatol., Vol.98 (6), pp.856-63 (1992); Santi et al., “Drug Reservoir Composition and Transport of Salmon Calcitonin in Transdermal Iontophoresis”, Pharm. Res., Vol 14 (1), pp.63-66 (1997); Santi et al., “Reverse Iontophoresis - Parameters Determining Electroosmotic Flow: I. pH and Ionic Strength”, J. Control. Release, Vol.38, pp.159-165 (1996); Santi et al., “Reverse Iontophoresis - Parameters Determining Electroosmotic Flow: II. Electrode Chamber Formulation”, J. Control. Release, Vol.42, pp.29-36 (1996); Rao et al., “Reverse Iontophoresis: Noninvasive Glucose Monitoring in vivo in Humans”, Pharm. Res., Vol.12 (12), pp.1869-1873 (1995); Thysman et al., “Human Calcitonin Delivery in Rats by Iontophoresis”, J. Pharm. Pharmacol., Vol.46, pp. 725-730 (1994); and Volpato et al., “Iontophoresis Enhances the Transport of Acyclovir through Nude Mouse Skin by Electrorepulsion and Electroosmosis”, Pharm. Res., Vol.12 (11), pp. 1623-1627 (1995).

[0171] A compound as described herein may be included in kits comprising a compound as described herein, a systemic or topical composition described above, or both; and information, instructions, or both that use of the kit will provide treatment for conditions including, for example, hair and skin conditions related to abnormal FPS units including PFB, AKN, HS, DCS, acne vulgaris, and combinations thereof in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. In addition, or in the alternative, the kit may comprise a compound as described herein, a composition as described herein, or both; and information, instructions, or both, regarding methods of application of the compound or composition, preferably with the benefit of treating hair and skin conditions related to abnormal FPS units in mammals.

[0172] In all of the foregoing compositions, and for all routes of administration, a compound as described herein can be used alone or in combinations of two or more compounds described herein. The compositions may further comprise additional drugs or excipients as appropriate for the specific condition or indication.Attorney Docket No.206314-0002-WO01 4. Methods

[0173] This disclosure further relates to methods for treating hair and skin conditions related to abnormal FPS units including PFB, AKN, HS, DCS, acne vulgaris, combinations thereof and the pigmentary changes related to these conditions occurring in mammals. The methods comprise administering to a mammal (preferably a human) a compound or composition as described herein. For example, a mammal diagnosed with PFB, AKN, HS, DCS, acne vulgaris, or a combination thereof may be treated by the methods of this disclosure. The methods as described herein may treat the hair and skin conditions related to abnormal FPS units by decreasing or inhibiting hair growth and / or decreasing the diameter of hairs in particular areas of a subject or decreasing the pigmentary changes related to the condition.

[0174] Preferably, a topical composition as described herein may be administered to the mammal. A compound or composition as described herein may be administered orally or applied topically to the scalp, eyebrows, beard, moustache, body hair, skin of any part of the body, or a combination thereof. The compound or composition may be administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 days. The topical composition is typically administered from once per day up to four times per day.

[0175] The dosage of a compound as described herein administered to a subject depends on the method of administration. For systemic administration, (e.g., oral, rectal, nasal, sublingual, buccal, or parenteral), typically, 0.1 mg to 300 mg, preferably 0.5 mg to 100 mg, more preferably 0.1 mg to 10 mg, of a compound described herein may be administered per day. These dosage ranges are merely exemplary, and daily administration can be adjusted depending on various factors. The specific dosage of the compound to be administered, as well as the duration of treatment, and whether the treatment is topical or systemic are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific compound used, the treatment indication, the efficacy of the compound, the personal attributes of the subject (such as, for example, weight, age, sex, and medical condition of the subject), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.

[0176] For topical administration (e.g., local application on the skin, ocular, liposome delivery systems, intralesional injections, shampoos, lotions, solutions, with agents such as low- level laser that increase absorption, or iontophoresis), a compound as described herein or topical composition may typically be administered from once per day up to six times per day. The compound or composition may be administered once, twice, three, four, five, or six times daily. The compound or composition may be administered daily to weekly. 0.0001 g to about 25 g of the compound of composition may be administered to a subject per day. 0.5 g to about 1.0 g of the compound or composition may be administered to a subject per day.Attorney Docket No.206314-0002-WO01 5. Examples

[0177] The foregoing may be better understood by reference to the following examples, which are presented for purposes of illustration and are not intended to limit the scope of the invention. The present disclosure has multiple aspects and embodiments, illustrated by the appended non-limiting examples. The following examples are prophetic. Example 1

[0178] Compositions for topical administration may be made, comprising:Attorney Docket No.206314-0002-WO01

[0179] According to the methods described herein, a subject may be treated with the above composition. Specifically, for 16 weeks or longer, one of the above compositions will be administered daily, topically to the subject Example 2

[0180] A composition for topical administration may be made according to the method of Dowton et al., “Influence of Liposomal Composition on Topical Delivery of Encapsulated Cyclosporin A: I. An in vitro Study Using Hairless Mouse Skin”, S.T.P. Pharma Sciences, Vol.3, pp.404 - 407 (1993), using a compound as described herein in lieu of cyclosporin A and using the NOVASOME® 1 (available from Micro-Pak, Inc. of Wilmington, Delaware) for the non-ionic liposomal formulation. According to the methods described herein, a subject may be treated with the above composition. Specifically, for 16 weeks or longer, the above composition will be administered topically to the subject with the effect on the condition and / or any associated pigmentary changes assessed Example 3

[0181] Shampoos and / or body washes may be made, comprising:Attorney Docket No.206314-0002-WO01

[0182] According to the methods described herein, a subject may be treated with one or more of the above compositions. Specifically, for 12 weeks or longer, a shampoo or body-wash selected from the ones described above will be used daily by the subject. Example 4

[0183] Shampoos and / or body washes may be made according to Example 3. A human subject who may have a hair or skin condition related to abnormal FPS units including PFB, AKN, HS, DCS, acne vulgaris, or combinations thereof may be treated by a method as described herein. Specifically, for days to several weeks, a shampoo and / or body wash selected from the ones described above may be used daily by the subject by applying to the scalp and / or body. Solution may also be applied to the face, and body hair. The treatment will be effective in treating the hair or skin condition related to abnormal FPS units as described herein and associated pigmentary changes.Attorney Docket No.206314-0002-WO01 Example 5

[0184] A simple topical composition may be prepared by combining the following components utilizing conventional mixing techniques:

[0185] This composition will be applied twice daily to the skin or hair as appropriately needed, in an amount sufficient to deposit about 0.5 ^g / cm2of the active compound to the skin for six months. The ability of the composition to treat hair and skin conditions related to abnormal FPS units (e.g., PFB, AKN, HS, DCS, acne vulgaris) and any pigmentary change induced by the condition, will be assessed and determined. Example 6

[0186] A cream may be prepared by combining the following components using conventional mixing techniques:Attorney Docket No.206314-0002-WO01

[0187] The first three phases are mixed with the active solution. The composition will be applied to the skin as appropriately needed once every other day for two months to treat hair and skin conditions related to abnormal FPS units (e.g., PFB, AKN, HS, DCS, acne vulgaris) and any associated pigmentary changes. Example 7

[0188] A nonionic oil-in-water emulsion may be prepared by combining the following components using conventional mixing techniques:

[0189] The composition will be applied to the skin or hair as appropriately needed once a day for four months. Use of an amount sufficient to deposit about 15 ^g of the activeAttorney Docket No.206314-0002-WO01 compound per cm2skin or hair should be appropriate. The ability of the composition to treat hair and skin conditions related to abnormal FPS units (e.g., PFB, AKN, HS, DCS, acne vulgaris) and any associated pigmentary changes will be assessed and determined. Example 8

[0190] A sunscreen composition may be prepared by combining the following components utilizing conventional mixing techniques:

[0191] The above composition will be applied to the skin twice a week for five months. Use of an amount sufficient to deposit about 100 ^g of the active compound per cm2skin should be appropriate. The ability of the composition to treat hair and skin conditions related to abnormal FPS units (e.g., PFB, AKN, HS, DCS, acne vulgaris) and any associated pigmentary changes will be assessed and determined. Example 9

[0192] A composition may be prepared by combining the following components utilizing conventional mixing techniques:Attorney Docket No.206314-0002-WO01

[0193] The above composition will be applied once to the skin or hair as appropriately needed (e.g., daily, every 2 days, every 3 days, etc.) for three months. Use of an amount sufficient to deposit about 120 ^g of the active compound per cm2skin or hair should be appropriate to treat hair and skin conditions related to abnormal FPS units (e.g., PFB, AKN, HS, DCS, acne vulgaris) and any associated pigmentary changes. Example 10 Pseudofolliculitis barbae (PFB)

[0194] An efficacy and safety study will be conducted in male African American patients with a history of PFB. An area of PFB will be designated in the beard area. A composition comprising a compound as described herein will be compared with the vehicle of the composition without a compound as described herein (i.e., Placebo).

[0195] During weeks 1-6 of the study, the Placebo will be applied daily to one side of the beard area including neck in a given patient with PFB and the composition comprising a compound as described herein will be applied to the other side of the beard / neck, and the areas will then be shaved daily with a standard razor.. During weeks 7-12 of the study, those sides being treated daily with Placebo will then be treated with the composition comprising a compound as described herein, and those sides being treated with the composition comprising a compound as described herein will continue to have this preparation applied daily. Areas will continue to be shaved daily with a standard razor. Efficacy of the composition comprising a compound as described herein vs. Placebo in PFB will then be assessed.

[0196] Efficacy of the composition comprising a compound as described herein will be based on: (1) the change from baseline in number of PFB bumps in the areas treated with Placebo vs. the composition comprising a compound as described herein; and (2) the perception of irritation in the areas receiving Placebo vs. the composition comprising a compound as described herein.

[0197] It is anticipated that the composition comprising a compound as described herein will result in patients having at least 20% less PFB bumps within 6 weeks of treatment as compared to the Placebo. It is also anticipated that the composition comprising a compound as described herein will result in a patient perception of silkier hairs, less hair trapping in skin, and less irritation overall as compared to the Placebo.Attorney Docket No.206314-0002-WO01

[0198] A longer application period of 12-24 weeks of the composition comprising a compound is needed to assess the effect on any pigmentary change associated with the condition Example 11 Acne keloidalis nuchae (AKN)

[0199] An efficacy and safety study will be conducted in male African American patients with a history of early AKN. The inferior occiput involved area with AKN will be designated. A composition comprising a compound as described herein will be compared with the vehicle of the composition without a compound as described herein (i.e., Placebo).

[0200] During weeks 1-6 of the study, Placebo will be applied daily to the inferior occiput involved area. Shaving of the affected area of the occiput with an electric razor will occur twice a week. During weeks 7-12 of the study, all patients will apply a composition comprising a compound as described herein to the same designated area. Shaving of the affected area of the occiput with an electric razor will occur twice a week. Efficacy of the composition comprising a compound as described herein against AKN will then be assessed.

[0201] Efficacy of the composition comprising a compound as described herein will be based on: (1) the change from baseline in AKN lesion count and distribution during the time patient was applying Placebo to the involved occiput vs. the time in which a composition comprising a compound as described herein was applied; and (2) the perception of pain and pruritus during the time the patient was applying Placebo vs. the time the patient was applying a composition comprising a compound as described herein.

[0202] It is anticipated that the composition comprising a compound as described herein will result in patients having at least 20% less AKN lesion bumps within 6 weeks of treatment as compared to the Placebo. It is also anticipated that the composition comprising a compound as described herein will result in a patient perception of less pain and pruritus overall as compared to the Placebo. Example 12 Hidradenitis supporativa (HS)

[0203] An efficacy and safety study will be conducted in female patients with moderately severe HS. The study will be an exploratory, randomized, double-blind, placebo-controlled study. A composition comprising a compound as described herein will be compared with a vehicle composition without a compound as described herein (i.e., Placebo).Attorney Docket No.206314-0002-WO01

[0204] Placebo or a composition comprising a compound as described herein will be applied twice daily for 12 weeks to the axillary areas of patients affected with HS. At the end of week 12, efficacy of the composition comprising a compound as described herein against Placebo in HS will be assessed.

[0205] Biopsies of an affected area will be completed at baseline and translational analysis will be performed to identify IL-17A-producing cells and indications of IL-17A activity in HS lesion skin. It is anticipated that the composition comprising a compound as described herein will result in a decrease in IL-17A expression and activity as compared to Placebo.

[0206] It is also anticipated that patients treated with the composition comprising a compound as described herein will result in at least a 20% increase in the number of patients with a Hidradenitis Suppurativa Clinical Response (HiSCR) score by week 12 as compared to those treated with Placebo. The HiSCR is defined as an at least 50% reduction in inflammatory lesion count (abscesses + inflammatory nodules), with no increase in abscesses or draining fistulas when compared with baseline.

[0207] Further, it is anticipated that patients treated with the composition comprising a compound as described herein will result in a reduction from baseline in a skin pain score, an improvement in HS-Physician Global Assessment (HS-PGA) responder rate, and an improvement in modified Sartorius score as compared to those treated with Placebo.

[0208] Further, it is anticipated that patients treated with the composition comprising a compound as described herein will result in a reduction from baseline in the score of abscess or subq tracts as assessed by ultrasound as compared to those treated with Placebo. Example 13 Dissecting cellulitis of the scalp (DCS)

[0209] An exploratory, randomized, double-blind, placebo-controlled efficacy and safety study will be conducted in male or female African American patients with a history of early dissecting cellulitis of the scalp (DCS). A composition comprising a compound as described herein will be compared with a vehicle composition without a compound as described herein (i.e., Placebo).

[0210] During weeks 1-12 of the study, either Placebo or a composition comprising a compound as described herein will be applied daily to the affected parts of the scalp either in a lotion, solution, or shampoo form that can be left applied at least overnight. Efficacy of the composition comprising a compound as described herein against DCS vs. Placebo will then be assessed.Attorney Docket No.206314-0002-WO01

[0211] Efficacy of the composition comprising a compound as described herein will be based on: (1) the change from baseline in nodules, abscesses, papules, pustules, and partial or total regrowth of hair in the patient group receiving Placebo vs. the patient group receiving a composition comprising a compound as described herein; and (2) the perception of pain and pruritus in the patient group receiving Placebo vs. the patient group receiving a composition comprising a compound as described herein.

[0212] It is anticipated that the composition comprising a compound as described herein will result in patients having at least 20% less pain and pruritus overall as compared to Placebo. Example 14 Acne vulgaris

[0213] A 12-24 week efficacy and safety study will be conducted in patients with moderately severe acne. The study will be a randomized, blinded, placebo-controlled study. A composition comprising a compound as described herein will be compared with a vehicle composition without a compound as described herein (i.e., Placebo).

[0214] To assess the efficacy of the composition comprising a compound as described herein against acne, the total number and the type of acne lesions (e.g., blackheads, whiteheads, red inflammatory patches of skin, etc.) will be compared post treatment between the two treatment groups of patients. In addition, any change in the hyperpigmentation associated with the acne vulgaris will be compared between the two treatment groups.

[0215] It is anticipated that those patients treated with the composition comprising a compound as described herein will have a lower total number of acne lesions or a decrease in the amount of inflammatory vs. non-inflammatory lesions as compared to those patients treated with Placebo. It is also anticipated that the composition comprising a compound as described herein will result in less severe acne lesions in those so treated as compared to those patients treated with Placebo and a greater change in any pigmentary change related to the condition. Example 15 Decreasing Pigmentary Changes A composition comprising a compound as described herein may be tested for ability to decrease or reduce changes in pigmentation of the skin resulting from a condition identified herein using a minolta meter CM-SA (Konica Minolta Sensing Americas, Inc., Ramsey, NJ; konicaminolta.com / sensingusa / products / Color-Measurement / specialty-meters-med-pers / CM- SA / index.html). Used in combination with a Konica Minolta spectrophotometer, the CM-SA enables highly accurate measurement of skin color simultaneously with a numerical display ofAttorney Docket No.206314-0002-WO01 the Melanin Index, Hb (Hemoglobin) Index, and Hb SO2(Hemoglobin oxygen saturation) Index (%). Measurement will be performed by simply placing the head of spectrophotometer against the skin of the subject and pressing the button. Measurements will be taken before and after a treatment regimen. After a treatment regimen as described, e.g., in an example herein, the melanin index shows change of pigmentation. A delta L value (change in the value of L) of 5 points is typically evidence of significant skin lightening. ***

[0216] The breadth and scope of the present disclosure should not be limited by any of the above-described exemplary aspects, but should be defined only in accordance with the following claims and their equivalents.

[0217] All publications, patents, patent applications, and / or other documents cited in this application are incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application, and / or other document were individually indicated to be incorporated by reference for all purposes.

[0218] For reasons of completeness, various aspects of the invention are set out in the following numbered clauses:

[0219] Clause 1. A method of treating a hair or skin condition related to abnormal folliculopilosebaceous (FPS) units, the method comprising administering to a subject in need thereof, a safe and effective amount of a compound described herein.

[0220] Clause 2. The method of clause 1, wherein the hair or skin condition related to abnormal FPS units comprises pseudofolliculitis barbae (PFB), acne keloidalis nuchae (AKN), hidradenitis suppurativa (HS), dissecting cellulitis of the scalp (DCS), acne vulgaris, combinations thereof, or associated pigmentary changes related thereto.

[0221] Clause 3. The method of clause 1, wherein the compound is an FP receptor antagonist.

[0222] Clause 4. The method of clause 3, wherein the FP receptor antagonist is selected from the group including OBE002, OBE022, and BAY-6672.

[0223] Clause 5. The method of clause 3, wherein the FP receptor antagonist is a compound of formula (II), or a pharmaceutically acceptable salt thereof,Attorney Docket No.206314-0002-WO01is tert-butyl or phenyl, wherein the phenyl is optionally substituted with 1-3 R1a; R1a, at each occurrence, is independently C1-4alkyl, C1-4fluoroalkyl, halogen, cyano, –OC1-4alkyl, or –OC1-4fluoroalkyl; R2is –C1-4alkylene–OH, –C1-4alkylene–OC1-4alkyl; –C1-4alkylene–OC(O)CH(NH2)R2a; R2ais hydrogen, C1-4alkyl,4alkylene–C3-6cycloalkyl, –C1-4alkylene–OH, or –C1-4alkylene–OC1-4alkyl; R3, at each occurrence, is independently C1-4alkyl, C1-4fluoroalkyl, halogen, cyano, –OC1-4alkyl, or –OC1-4fluoroalkyl; R4, at each occurrence, is independently C1-4alkyl or C1-4fluoroalkyl; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4.

[0224] Clause 6. The method of clause 3, wherein the FP receptor antagonist is a compound of formula (III), or a pharmaceutically acceptable salt thereof,wherein: Ar is phenyl or pyridinyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents, the pyridinyl is unsubstituted or substituted with 1-2 substituents, and the substituents are independently selected from the group consisting of fluoro, chloro, C1-4alkyl, C3-4cycloalkyl, –OC1-2alkyl, –SC1-2alkyl, C1-4alkyl substituted by 1-3 fluoro, C3-4cycloalkyl substituted by 1-4 fluoro, –OC1-2alkyl substituted by 1-3 fluoro, –SC1-2alkyl substituted by 1-3 fluoro, or where two substituents of the phenyl or pyridinyl on adjacent ring atoms together form a methylenedioxy or ethylenedioxy; L is a bond or –X– (CRaRb)k–; X is a bond, CH2, O, S, S(O), S(O)2, or N(R); R is hydrogen or CH3; Raand Rbare independently hydrogen, fluoro, or CH3; or Raand Rbtogether with the carbon atom to which they attach form a cyclopropyl; k is 1, 2, 3, or 4; R10is halogen, C1-4alkyl, C1-4alkyl substituted byAttorney Docket No.206314-0002-WO01 1-5 fluoro, –OCH3, –OCH2F, –OCHF2, –OCF3, –SCF3, –SF5, –SiCH3, ethynyl, cyclopropyl, or cyclobutyl, where the cyclopropyl and cyclobutyl are unsubstituted or substituted by 1-4 fluoro; R20, R30, and R40are independently hydrogen, halogen, CH3, CH2F, CHF2, or CF3; R50is halogen, C1-4alkyl, C1-4alkyl substituted by 1-5 fluoro, –OCH3, –OCH2F, –OCHF2, –OCF3, OH, – SCH3, –SCF3, cyano, ethenyl, cyclopropyl, or cyclobutyl, where the cyclopropyl and cyclobutyl are unsubstituted or substituted by 1-4 fluoro; R60is –NRcRd; Rcis hydrogen or C1-3alkyl; Rdis C1-4alkyl, C3-7cycloalkyl, C1-4alkyl substituted by 1-5 fluoro, C1-4alkyl monosubstituted by C3-6cycloalkyl, –OCH3, –OCF3, or phenyl, wherein the C3-7cycloalkyl is optionally substituted with 1- 4 fluoro; or Rcand Rdtogether with the nitrogen to which they attach form a saturated or partially unsaturated 4- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocyclic ring, the heterocyclic rings optionally containing a ring member selected from the group consisting of O, N, S, SO, and S(O)2, wherein the heterocyclic rings are optionally substituted with 1-4 substituents independently selected from the group consisting of fluoro, C1-4alkyl, OH, oxo, –OC1-3alkyl, –OCHF2, –OCF3, cyano, NH2, NHCH3, N(CH3)2, C(O)NH2, C(O)NHCH3, C(O)N(CH3)2, C1-4alkyl substituted with 1-5 fluoro, and C1-4alkyl monosubstituted with OH or – OCH3; R70Aand R70Bare independently hydrogen or CH3, or R70Aand R70Btogether with the carbon atom to which they attach form a cyclopropyl; R80is hydrogen, fluoro, CH3, CF3, CH2CH3, or OH; and R90is hydrogen or CH3.

[0225] Clause 7. The method of clause 3, wherein the FP receptor antagonist is a compound of formula (IV) or formula (V):wherein R is selected from the group consisting of CO2H, C(O)NHOH, CO2R1, CH2OH, S(O)2R1, C(O)NHR1, P(O)(OR1) R2, C(O)NHS(O)2R1, and tetrazole; R1and R2are independently selected from the group consisting of a hydrogen atom, monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, aromatic groups, substituted aromatic groups, carbocyclic groups, substituted carbocyclic groups, heterogeneous groups, substituted heterogeneous groups, heterocyclic groups, substituted heterocyclic groups, heteroaromatic groups, and substituted heteroaromatic groups; W is -CH2-, -O-, or -S(O)2-; and X is halogen, lower alkyl, alkoxy, or hydrogen.Attorney Docket No.206314-0002-WO01

[0226] Clause 8. The method of clause 7, wherein R1and R2are selected from the group consisting of CH3, C2H5, and C3H7.

[0227] Clause 9. The method of clause 7 or 8, wherein R is selected from the group consisting of CO2H, CO2CH3, C(O)NHC2H5, CO2C2H5, CO2C3H7, CO2C4H9, CO2C3H7O2, and C(O)NHS(O)2R1.

[0228] Clause 10. The method of clause 9, wherein R is selected from the group consisting of CO2H, CO2CH3, CO2C2H5, C(O)NHC2H5, and CO2C3H7.

[0229] Clause 11. The method of clause 10, wherein R is selected from the group consisting of CO2H, CO2CH3, C(O)NHC2H5, and CO2C3H7.

[0230] Clause 12. The method of any one of clauses 7-11, wherein X is methoxy.

[0231] Clause 13. The method of any one of clauses 7-11, wherein X is methyl.

[0232] Clause 14. The method of any one of clauses 7-11, wherein X is halogen.

[0233] Clause 15. The method of clause 14, wherein X is F.

[0234] Clause 16. The method of clause 7, wherein the compound is a 11-deoxy-16-fluoro PGF2αanalog.

[0235] Clause 17. The method of clause 7, wherein the compound is the following:.

[0236] Clause 18. The method of clause 7, wherein the compound is the following:Attorney Docket No.206314-0002-WO01

[0237] Clause 19. The method of clause 7, wherein the compound is the following:.

[0238] Clause 20. The method of clause 3, wherein the FP receptor antagonist is a compound of formula (VI):wherein G is selected from the group consisting of substituted or unsubstituted C1-C6-alkyl aryl, substituted or unsubstituted C1-C6-alkyl heteroaryl, substituted or unsubstituted C1-C6-alkyl cycloalkyl, substituted or unsubstituted C1-C6-alkyl heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, wherein said cycloalkyl or aryl or heteroaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups; R1is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, wherein said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (hetero)-cycloalkyl or aryl or heteroaryl groups; R2is H, carboxy, acyl, alkoxycarbonyl, aminocarbonyl, substituted or unsubstituted C1-C5-alkyl carboxy, substituted or unsubstituted C1-C5-alkyl acyl, substituted or unsubstituted C1-C5-alkyl alkoxycarbonyl, substituted or unsubstituted C1-C5-alkyl aminocarbonyl, substituted or unsubstituted C1-C5-alkyl acyloxy, substituted or unsubstituted C1-C5-alkyl acylamino, substituted or unsubstituted C1-C5-alkyl ureido, substituted or unsubstituted C1-C5-alkyl amino, substituted or unsubstituted C1-C5-alkyl alkoxy, substituted or unsubstituted C1-C5-alkyl sulfanyl, substituted or unsubstituted C1-C5-alkyl sulfinyl, substituted or un substituted C1-C5-alkyl sulfonyl, substituted or unsubstituted C1-C5-alkyl sulfonylamino, substituted or unsubstituted C1-C5-alkyl sulfonyloxy, substituted or unsubstituted C1-C6-alkyl,Attorney Docket No.206314-0002-WO01 substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C1-C6-a1kyl aryl, substituted or unsubstituted C2-C6-alkyl heteroaryl, substituted or unsubstituted C1-C6-alkyl cycloalkyl, substituted or unsubstituted C1-C6-alkyl heterocycloalkyl, substituted or unsubstituted C2-C6-alkenyl aryl, substituted or unsubstituted C2-C6-alkenyl heteroaryl, substituted or unsubstituted C2-C6-alkynyl aryl, or substituted or unsubstituted C2-C6- alkynyl heteroaryl, or wherein R2and G may form a C3-C8-cycloalkyl ring; R4is selected from the group consisting of substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted C2- C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl; and n is an integer from 0 to 2.

[0239] Clause 21. The method of clause 20, wherein G is an aryl group.

[0240] Clause 22. The method of clause 20, wherein G is a substituted or unsubstituted phenyl.

[0241] Clause 23. The method of clause 20, wherein G is a biphenyl.

[0242] Clause 24. The method of clause 20, wherein the compound is the following:.

[0243] Clause 25. The method of clause 3, wherein the FP receptor antagonist is a compound of formula (VII): Y-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-Z (VII) wherein Y is attached to the amino-terminus of said peptide and is selected from the group consisting of a hydrogen atom, an acetyl group, a benzoyl group, an acyl group (R--CO--) wherein R is a hydrophobic moiety, and an aroyl group (Ar--CO--) wherein Ar is an aryl group; AA1and AA2are independently selected from the group consisting of no residue, isoleucine (Ile), leucine (Leu), and related alpha-amino acids possessing hydrophobic side-chains; AA3is selected from the group consisting of no residue, glycine (Gly), alanine (Ala), and proline (Pro); AA4 is selected from the group consisting of histidine (His), phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp); AA5is selected from the group consisting of arginine (Arg), ornithine (Orn), lysine (Lys),Attorney Docket No.206314-0002-WO01 citruline, 2-, 3-, and 4-pyridylalanine, and arginine surrogates; AA6is selected from the group consisting of aspartic acid (Asp), asparagine (Asn), glutamic acid (Glu), glutamine (Gln), serine (Ser), 3-amino-5-phenylpentanoic acid, and Phe; AA7 is selected from the group consisting of no residue, Tyr, and Phe; AA8is selected from the group consisting of no residue, Lys, Leu, and Tyr; and Z is attached to the carboxy-terminus of said peptide and is selected from the group consisting of, a hydroxyl group, NH2, and aromatic and aliphatic amines.

[0244] Clause 26. The method of clause 25, wherein the FP receptor antagonist comprises a polypeptide of SEQ ID NO: 1.

[0245] Clause 27. The method of clause 3, wherein the FP receptor antagonist is a compound of formula (VIII): Y-BTM-AA1-AA2-AA3-Z (VIII) wherein Y is attached to the amino- terminus of the peptide and is selected from the group consisting of a hydrogen atom, an acyl group (R--CO--) wherein R is a hydrophobic moiety, and an aroyl group (Ar--CO--) wherein Ar is an aryl group; BTM (beta turn mimetic) is a dipeptide surrogate; AA1is selected from the group consisting of Arg, Orn, Lys, citruline, 2-, 3-, and 4-pyridylalanine, and arginine surrogates; AA2is selected from the group consisting of Asp, Asn, Glu, Gln, Ser, 3-amino-5-phenylpentanoic acid, and Phe; AA3is selected from the group consisting of no residue, Tyr, and Phe; and Z is selected from the group consisting of no residue, a hydroxyl group, NH2, and aromatic, heteroaromatic, and aliphatic amines.

[0246] Clause 28. The method of clause 1, wherein the compound is an ornithine decarboxylase inhibitor selected from the group including 2-(difluoromethyl)-2,5- diaminopentanoic acid; alpha-ethynyl ornithine; 6-heptyne-2,5-diamine; and 2-methyl-6-heptyne diamine.

[0247] Clause 29. The method of clause 28, wherein the ornithine decarboxylase inhibitor is eflornithine hydrochloride.

[0248] Clause 30. The method of clause 28 or 29, wherein 0.0001 g to about 25.0 g of the compound is administered to the subject per day.

[0249] Clause 31. The method of any one of clauses 1-30, wherein the compound is topically or orally administered to the subject.

[0250] Clause 32. The method of clause 31, wherein the compound is administered to the subject in one or more of an intralesional injection, shampoo, lotion, solution, oil, cream, ointment, gel, leave-on and rinse-out hair conditioners, milk, cleanser, moisturizer, mousse, spray, foam, skin patches, or the like.

[0251] Clause 33. The method of clause 32, wherein the compound is administered to the subject’s scalp, eyebrows, beard, moustache, body hair, skin, or combinations thereof.Attorney Docket No.206314-0002-WO01

[0252] Clause 34. The method of any one of clauses 1-33, wherein the compound is administered for about 6 weeks to about 10 weeks.

[0253] Clause 35. The method of any one of clauses 1-34, wherein PFB is treated in the subject.

[0254] Clause 36. The method of any one of clauses 1-35, wherein AKN is treated in the subject.

[0255] Clause 37. The method of any one of clauses 1-36, wherein HS is treated in the subject.

[0256] Clause 38. The method of any one of clauses 1-37, wherein DCS is treated in the subject.

[0257] Clause 39. The method of any one of clauses 1-38, wherein acne vulgaris is treated in the subject.

[0258] Clause 40. The method of any one of clauses 1-39, wherein the compound inhibits or decreases hair growth in the subject.

[0259] Clause 41. The method of any one of clauses 1-40, wherein the compound decreases the diameter of hairs in the subject.

[0260] Clause 42. The method of any one of claims 1-41, wherein the associated pigmentary changes related to pseudofolliculitis barbae (PFB), acne keloidalis nuchae (AKN), hidradenitis suppurativa (HS), dissecting cellulitis of the scalp (DCS), acne vulgaris, or a combination thereof is decreased in the subject.

Claims

Attorney Docket No.206314-0002-WO01 CLAIMS What is claimed is:

1. A method of treating a hair or skin condition related to abnormal folliculopilosebaceous (FPS) units, the method comprising administering to a subject in need thereof, a safe and effective amount of a compound described herein.

2. The method of claim 1, wherein the hair or skin condition related to abnormal FPS units comprises pseudofolliculitis barbae (PFB), acne keloidalis nuchae (AKN), hidradenitis suppurativa (HS), dissecting cellulitis of the scalp (DCS), acne vulgaris, combinations thereof or associated pigmentary changes related thereto.

3. The method of claim 1, wherein the compound is an FP receptor antagonist.

4. The method of claim 3, wherein the FP receptor antagonist is selected from the group including OBE002, OBE022, and BAY-6672.

5. The method of claim 3, wherein the FP receptor antagonist is a compound of formula (II), or a pharmaceutically acceptable salt thereof,R1is tert-butyl or phenyl, wherein the phenyl is optionally substituted with 1-3 R1a; R1a, at each occurrence, is independently C1-4alkyl, C1-4fluoroalkyl, halogen, cyano, –OC1-4alkyl, or –OC1-4fluoroalkyl;Attorney Docket No.206314-0002-WO01 R2is –C1-4alkylene–OH, –C1-4alkylene–OC1-4alkyl; –C1-4alkylene–OC(O)C1-4alkyl, or –C1-4alkylene–OC(O)CH(NH2)R2a; R2ais hydrogen, C1-4alkyl, C1-4fluoroalkyl, C3-6cycloalkyl, –C1-4alkylene–C3-6cycloalkyl, –C1- 4alkylene–OH, or –C1-4alkylene–OC1-4alkyl; R3, at each occurrence, is independently C1-4alkyl, C1-4fluoroalkyl, halogen, cyano, –OC1-4alkyl, or –OC1-4fluoroalkyl; R4, at each occurrence, is independently C1-4alkyl or C1-4fluoroalkyl; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4.

6. The method of claim 3, wherein the FP receptor antagonist is a compound of formula (III), or a pharmaceutically acceptable salt thereof,wherein: Ar is phenyl or pyridinyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents, the pyridinyl is unsubstituted or substituted with 1-2 substituents, and the substituents are independently selected from the group consisting of fluoro, chloro, C1-4alkyl, C3-4cycloalkyl, –OC1-2alkyl, –SC1-2alkyl, C1-4alkyl substituted by 1-3 fluoro, C3- 4cycloalkyl substituted by 1-4 fluoro, –OC1-2alkyl substituted by 1-3 fluoro, –SC1-2alkyl substituted by 1-3 fluoro, or where two substituents of the phenyl or pyridinyl on adjacent ring atoms together form a methylenedioxy or ethylenedioxy; L is a bond or –X–(CRaRb)k–; X is a bond, CH2, O, S, S(O), S(O)2, or N(R); R is hydrogen or CH3; Raand Rbare independently hydrogen, fluoro, or CH3; or Raand Rbtogether with the carbon atom to which they attach form a cyclopropyl; k is 1, 2, 3, or 4;Attorney Docket No.206314-0002-WO01 R10is halogen, C1-4alkyl, C1-4alkyl substituted by 1-5 fluoro, –OCH3, –OCH2F, –OCHF2, –OCF3, –SCF3, –SF5, –SiCH3, ethynyl, cyclopropyl, or cyclobutyl, where the cyclopropyl and cyclobutyl are unsubstituted or substituted by 1-4 fluoro; R20, R30, and R40are independently hydrogen, halogen, CH3, CH2F, CHF2, or CF3; R50is halogen, C1-4alkyl, C1-4alkyl substituted by 1-5 fluoro, –OCH3, –OCH2F, –OCHF2, –OCF3, OH, –SCH3, –SCF3, cyano, ethenyl, cyclopropyl, or cyclobutyl, where the cyclopropyl and cyclobutyl are unsubstituted or substituted by 1-4 fluoro; R60is –NRcRd; Rcis hydrogen or C1-3alkyl; Rdis C1-4alkyl, C3-7cycloalkyl, C1-4alkyl substituted by 1-5 fluoro, C1-4alkyl monosubstituted by C3-6cycloalkyl, –OCH3, –OCF3, or phenyl, wherein the C3-7cycloalkyl is optionally substituted with 1-4 fluoro; or Rcand Rdtogether with the nitrogen to which they attach form a saturated or partially unsaturated 4- to 8-membered monocyclic or 6- to 10-membered bicyclic heterocyclic ring, the heterocyclic rings optionally containing a ring member selected from the group consisting of O, N, S, SO, and S(O)2, wherein the heterocyclic rings are optionally substituted with 1-4 substituents independently selected from the group consisting of fluoro, C1-4alkyl, OH, oxo, –OC1-3alkyl, –OCHF2, –OCF3, cyano, NH2, NHCH3, N(CH3)2, C(O)NH2, C(O)NHCH3, C(O)N(CH3)2, C1-4alkyl substituted with 1-5 fluoro, and C1-4alkyl monosubstituted with OH or –OCH3; R70Aand R70Bare independently hydrogen or CH3, or R70Aand R70Btogether with the carbon atom to which they attach form a cyclopropyl; R80is hydrogen, fluoro, CH3, CF3, CH2CH3, or OH; and R90is hydrogen or CH3.

7. The method of claim 3, wherein the FP receptor antagonist is a compound of formula (IV) or formula (V):Attorney Docket No.206314-0002-WO01wherein R is selected from the group consisting of CO2H, C(O)NHOH, CO2R1, CH2OH, S(O)2R1, C(O)NHR1, P(O)(OR1) R2, C(O)NHS(O)2R1, and tetrazole; R1and R2are independently selected from the group consisting of a hydrogen atom, monovalent hydrocarbon groups, substituted monovalent hydrocarbon groups, aromatic groups, substituted aromatic groups, carbocyclic groups, substituted carbocyclic groups, heterogeneous groups, substituted heterogeneous groups, heterocyclic groups, substituted heterocyclic groups, heteroaromatic groups, and substituted heteroaromatic groups; W is -CH2-, -O-, or -S(O)2-; and X is halogen, lower alkyl, alkoxy, or hydrogen.

8. The method of claim 7, wherein R1and R2are selected from the group consisting of CH3, C2H5, and C3H7.

9. The method of claim 7 or 8, wherein R is selected from the group consisting of CO2H, CO2CH3, C(O)NHC2H5, CO2C2H5, CO2C3H7, CO2C4H9, CO2C3H7O2, and C(O)NHS(O)2R1.

10. The method of claim 9, wherein R is selected from the group consisting of CO2H, CO2CH3, CO2C2H5, C(O)NHC2H5, and CO2C3H7.

11. The method of claim 10, wherein R is selected from the group consisting of CO2H, CO2CH3, C(O)NHC2H5, and CO2C3H7.

12. The method of any one of claims 7-11, wherein X is methoxy.

13. The method of any one of claims 7-11, wherein X is methyl.Attorney Docket No.206314-0002-WO01 14. The method of any one of claims 7-11, wherein X is halogen.

15. The method of claim 14, wherein X is F.

16. The method of claim 7, wherein the compound is a 11-deoxy-16-fluoro PGF2αanalog.

17. The method of claim 7, wherein the compound is the following:.

18. The method of claim 7, wherein the compound is the following:.

19. The method of claim 7, wherein the compound is the following:Attorney Docket No.206314-0002-WO01.

20. The method of claim 3, wherein the FP receptor antagonist is a compound of formula (VI):wherein G is selected from the group consisting of substituted or unsubstituted C1-C6-alkyl aryl, substituted or unsubstituted C1-C6-alkyl heteroaryl, substituted or unsubstituted C1-C6- alkyl cycloalkyl, substituted or unsubstituted C1-C6-alkyl heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl or C3-C8-heterocycloalkyl, wherein said cycloalkyl or aryl or heteroaryl groups may be fused with cycloalkyl or aryl or heteroaryl groups; R1is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl or C3-C8- heterocycloalkyl, wherein said (hetero)cycloalkyl or aryl or heteroaryl groups may be fused with (hetero)-cycloalkyl or aryl or heteroaryl groups; R2is H, carboxy, acyl, alkoxycarbonyl, aminocarbonyl, substituted or unsubstituted C1-C5-alkyl carboxy, substituted or unsubstituted C1-C5-alkyl acyl, substituted or unsubstituted C1- C5-alkyl alkoxycarbonyl, substituted or unsubstituted C1-C5-alkyl aminocarbonyl, substituted or unsubstituted C1-C5-alkyl acyloxy, substituted or unsubstituted C1-C5-alkyl acylamino, substituted or unsubstituted C1-C5-alkyl ureido, substituted or unsubstitutedAttorney Docket No.206314-0002-WO01 C1-C5-alkyl amino, substituted or unsubstituted C1-C5-alkyl alkoxy, substituted or unsubstituted C1-C5-alkyl sulfanyl, substituted or unsubstituted C1-C5-alkyl sulfinyl, substituted or un substituted C1-C5-alkyl sulfonyl, substituted or unsubstituted C1-C5- alkyl sulfonylamino, substituted or unsubstituted C1-C5-alkyl sulfonyloxy, substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C8-cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted C1-C6-a1kyl aryl, substituted or unsubstituted C2-C6-alkyl heteroaryl, substituted or unsubstituted C1-C6-alkyl cycloalkyl, substituted or unsubstituted C1-C6-alkyl heterocycloalkyl, substituted or unsubstituted C2-C6-alkenyl aryl, substituted or unsubstituted C2-C6-alkenyl heteroaryl, substituted or unsubstituted C2-C6-alkynyl aryl, or substituted or unsubstituted C2-C6- alkynyl heteroaryl, or wherein R2and G may form a C3-C8-cycloalkyl ring; R4is selected from the group consisting of substituted or unsubstituted C1-C6-alkyl, substituted or unsubstituted C2-C6-alkenyl, substituted or unsubstituted C2-C6-alkynyl; and n is an integer from 0 to 2.

21. The method of claim 20, wherein G is an aryl group.

22. The method of claim 20, wherein G is a substituted or unsubstituted phenyl.

23. The method of claim 20, wherein G is a biphenyl.

24. The method of claim 20, wherein the compound is the following: .Attorney Docket No.206314-0002-WO01 25. The method of claim 3, wherein the FP receptor antagonist is a compound of formula (VII): Y-AA1-AA2-AA3-AA4-AA5-AA6-AA7-AA8-Z (VII) wherein Y is attached to the amino-terminus of said peptide and is selected from the group consisting of a hydrogen atom, an acetyl group, a benzoyl group, an acyl group (R--CO- -) wherein R is a hydrophobic moiety, and an aroyl group (Ar--CO--) wherein Ar is an aryl group; AA1and AA2are independently selected from the group consisting of no residue, isoleucine (Ile), leucine (Leu), and related alpha-amino acids possessing hydrophobic side-chains; AA3is selected from the group consisting of no residue, glycine (Gly), alanine (Ala), and proline (Pro); AA4is selected from the group consisting of histidine (His), phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp); AA5is selected from the group consisting of arginine (Arg), ornithine (Orn), lysine (Lys), citruline, 2-, 3-, and 4-pyridylalanine, and arginine surrogates; AA6is selected from the group consisting of aspartic acid (Asp), asparagine (Asn), glutamic acid (Glu), glutamine (Gln), serine (Ser), 3-amino-5-phenylpentanoic acid, and Phe; AA7is selected from the group consisting of no residue, Tyr, and Phe; AA8is selected from the group consisting of no residue, Lys, Leu, and Tyr; and Z is attached to the carboxy-terminus of said peptide and is selected from the group consisting of, a hydroxyl group, NH2, and aromatic and aliphatic amines.

26. The method of claim 25, wherein the FP receptor antagonist comprises a polypeptide of SEQ ID NO:

1.

27. The method of claim 3, wherein the FP receptor antagonist is a compound of formula (VIII): Y-BTM-AA1-AA2-AA3-Z (VIII) wherein Y is attached to the amino-terminus of the peptide and is selected from the group consisting of a hydrogen atom, an acyl group (R--CO--) wherein R is a hydrophobic moiety, and an aroyl group (Ar--CO--) wherein Ar is an aryl group; BTM (beta turn mimetic) is a dipeptide surrogate; AA1is selected from the group consisting of Arg, Orn, Lys, citruline, 2-, 3-, and 4-pyridylalanine, and arginine surrogates; AA2is selected from the group consisting of Asp, Asn, Glu, Gln, Ser, 3-amino-5- phenylpentanoic acid, and Phe; AA3is selected from the group consisting of no residue, Tyr, and Phe; andAttorney Docket No.206314-0002-WO01 Z is selected from the group consisting of no residue, a hydroxyl group, NH2, and aromatic, heteroaromatic, and aliphatic amines.

28. The method of claim 1, wherein the compound is an ornithine decarboxylase inhibitor selected from the group including 2-(difluoromethyl)-2,5-diaminopentanoic acid; alpha-ethynyl ornithine; 6-heptyne-2,5-diamine; and 2-methyl-6-heptyne diamine.

29. The method of claim 28, wherein the ornithine decarboxylase inhibitor is eflornithine hydrochloride.

30. The method of claim 28 or 29, wherein 0.0001 g to about 25.0 g of the compound is administered to the subject per day.

31. The method of any one of claims 1-30, wherein the compound is topically or orally administered to the subject.

32. The method of claim 31, wherein the compound is administered to the subject in one or more of an intralesional injection, shampoo, lotion, solution, oil, cream, ointment, gel, leave-on and rinse-out hair conditioners, milk, cleanser, moisturizer, mousse, spray, foam, skin patches, or the like.

33. The method of claim 32, wherein the compound is administered to the subject’s scalp, eyebrows, beard, moustache, body hair, skin, or combinations thereof.

34. The method of any one of claims 1-33, wherein the compound is administered for about 6 weeks to about 10 weeks.

35. The method of any one of claims 1-34, wherein PFB is treated in the subject.

36. The method of any one of claims 1-35, wherein AKN is treated in the subject.

37. The method of any one of claims 1-36, wherein HS is treated in the subject.

38. The method of any one of claims 1-37, wherein DCS is treated in the subject.

39. The method of any one of claims 1-38, wherein acne vulgaris is treated in the subject.Attorney Docket No.206314-0002-WO01 40. The method of any one of claims 1-39, wherein the compound inhibits or decreases hair growth in the subject.

41. The method of any one of claims 1-40, wherein the compound decreases the diameter of hairs in the subject.

42. The method of any one of claims 1-41, wherein the associated pigmentary changes related to pseudofolliculitis barbae (PFB), acne keloidalis nuchae (AKN), hidradenitis suppurativa (HS), dissecting cellulitis of the scalp (DCS), acne vulgaris, or a combination thereof is decreased in the subject.

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