WO2020160225A1 - ESTROGEN RECEPTOR BETA (ERβ) AGONISTS FOR THE TREATMENT OF FIBROTIC CONDITIONS - Google Patents

ESTROGEN RECEPTOR BETA (ERβ) AGONISTS FOR THE TREATMENT OF FIBROTIC CONDITIONS Download PDF

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WO2020160225A1
WO2020160225A1 PCT/US2020/015821 US2020015821W WO2020160225A1 WO 2020160225 A1 WO2020160225 A1 WO 2020160225A1 US 2020015821 W US2020015821 W US 2020015821W WO 2020160225 A1 WO2020160225 A1 WO 2020160225A1
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alkyl
fibrotic condition
fibrosis
agonist
group
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PCT/US2020/015821
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French (fr)
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Christopher Charles COSS
Chad BENNETT
Jeffrey Patrick
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Ohio State Innovation Foundation
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/065—Diphenyl-substituted acyclic alcohols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin

Definitions

  • the process of tissue repair as a part of wound healing involves two phases.
  • the first phase is the regenerative phase, in which injured cells are replaced by cells of the same type.
  • the second phase is the formation of fibrous tissues, also called fibroplasia or fibrosis, in which connective tissue replaces normal parenchymal tissues.
  • the tissue repair process can become pathogenic if the fibrosis phase continues unchecked, leading to extensive tissue remodeling and the formation of permanent scar tissue.
  • ILD interstitial lung disease
  • organ fibrotic disorders include liver cirrhosis, liver fibrosis resulting from chronic hepatitis B or C infection, kidney disease, heart disease, and eye diseases including macular degeneration and retinal and vitreal retinopathy. Fibroproliferative disorders also include systemic and local scleroderma, keloids and hypertrophic scars, atherosclerosis, and restenosis. Additional fibroproliferative diseases include excessive scarring resulting from surgery, chemotherapeutic drug-induced fibrosis, radiation-induced fibrosis, and injuries and burns.
  • the fibrotic condition can comprise a fibrotic condition of the liver, such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • Figure 1 illustrates the average body weight change observed in the four study groups over the course of the treatment period.
  • Figure 2A is a plot showing the body weight of animals on the day of sacrifice.
  • Figure 2B is a plot showing the liver weight of animals on the day of sacrifice.
  • Figure 2C is a plot showing the liver-to-body weight ratio of animals on the day of sacrifice.
  • Figure 3 A is a plot showing plasma alanine aminotransferase (ALT) levels (in U/L) on the day of sacrifice.
  • Figure 3B is a plot showing liver triglyceride levels (in mg/g liver) on the day of sacrifice.
  • Figure 4 is a plot showing the non-alcoholic fatty liver disease (NAFLD) activity score on the day of sacrifice.
  • NAFLD non-alcoholic fatty liver disease
  • Figure 5 A is a plot showing the steatosis score on the day of sacrifice.
  • Figure 5B is a plot showing the inflammation score on the day of sacrifice.
  • Figure 5C is a plot showing the ballooning score on the day of sacrifice.
  • Figure 6 is a plot showing the fibrosis area (sirius red-positive area, %) on the day of sacrifice.
  • Ranges can be expressed herein as from“about” one particular value, and/or to “about” another particular value. By“about” is meant within 5% of the value, e.g., within 4, 3, 2, or 1% of the value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
  • a“subject” is meant an individual.
  • the“subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g, cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g, mouse, rabbit, rat, guinea pig, etc.), and birds.
  • “Subject” can also include a mammal, such as a primate or a human.
  • the subject can be a human or veterinary patient.
  • the term“patient” refers to a subject under the treatment of a clinician, e.g., physician.
  • fibrotic condition refers to a disease or condition involving the formation and/or deposition of fibrous tissue, e.g., excessive connective tissue builds up in a tissue and/or spreads over or replaces normal organ tissue (reviewed in, e.g., Wynn, Nature Reviews 4:583-594 (2004) and Abdel-Wahab, O. et al. (2009) Annu. Rev. Med. 60:233-45, incorporated herein by reference).
  • the fibrotic condition involves excessive collagen mRNA production and deposition.
  • the fibrotic condition involves excessive collagen mRNA production and deposition.
  • the fibrotic condition is caused, at least in part, by injury, e.g., chronic injury (e.g., an insult, a wound, a toxin, a disease).
  • the fibrotic condition is associated with an inflammatory, an autoimmune or a connective tissue disorder.
  • chronic inflammation in a tissue can lead to fibrosis in that tissue.
  • Exemplary fibrotic tissues include, but are not limited to, biliary tissue, liver tissue, lung tissue, heart tissue, vascular tissue, kidney tissue, skin tissue, gut tissue, peritoneal tissue, bone marrow, and the like.
  • the tissue is epithelial tissue.
  • Treating,”“treat,” and“treatment” as used herein refers to partially or completely inhibiting or reducing the fibrotic condition which the subject is suffering.
  • this term refers to an action that occurs while a patient is suffering from, or is diagnosed with, the fibrotic condition, which reduces the severity of the condition, or retards or slows the progression of the condition. Treatment need not result in a complete cure of the condition; partial inhibition or reduction of the fibrotic condition is encompassed by this term.
  • “Therapeutically effective amount,” as used herein, refers to a minimal amount or concentration of an ERP agonist that, when administered alone or in combination, is sufficient to provide a therapeutic benefit in the treatment of the condition, or to delay or minimize one or more symptoms associated with the condition.
  • the term“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. The therapeutic amount need not result in a complete cure of the condition; partial inhibition or reduction of the fibrotic condition is encompassed by this term.
  • the terms“prevent,”“preventing” and “prevention” refers to an action that occurs before the subject begins to suffer from the condition, or relapse of such condition. The prevention need not result in a complete prevention of the condition; partial prevention or reduction of the fibrotic condition is encompassed by this term.
  • a“prophylactically effective amount” of a ERP that, when administered alone or in combination, prevent the condition, or one or more symptoms associated with the condition, or prevent its recurrence.
  • the term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. The prophylactic amount need not result in a complete prevention of the condition; partial prevention or reduction of the fibrotic condition is encompassed by this term.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • the term“substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • heteroatoms present in a compound or moiety, such as nitrogen can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valency of the heteroatom.
  • substitution or“substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound (e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • Z 1 ,”“Z 2 ,”“Z 3 ,” and“Z 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • alkyl refers to saturated, straight-chained or branched saturated hydrocarbon moieties. Unless otherwise specified, C1-C24 (e.g., C1-C22, C1-C2 0 , C1-C18, C1-C1 6 , C1-C14, C1-C12, C1-C10, C1-C8, C1-C 6 , or C1-C4) alkyl groups are intended.
  • alkyl groups include methyl, ethyl, propyl, 1 -methyl-ethyl, butyl, 1 -methyl- propyl, 2-methyl-propyl, 1,1 -dimethyl-ethyl, pentyl, 1 -methyl-butyl, 2-methyl-butyl, 3- methyl-butyl, 2,2-dimethyl-propyl, 1 -ethyl -propyl, hexyl, 1,1 -dimethyl-propyl, 1,2- dimethyl-propyl, 1 -methyl-pentyl, 2-methyl-pentyl, 3 -methyl-pentyl, 4-methyl-pentyl, 1,1- dimethyl -butyl , 1,2-dimethyl-butyl, 1,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, 3, 3 -dimethyl-butyl, 1 -ethyl-butyl,
  • Alkyl substituents may be unsubstituted or substituted with one or more chemical moieties.
  • the alkyl group can be substituted with one or more groups including, but not limited to, hydroxy, halogen, acyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied.
  • alkyl is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group.
  • halogenated alkyl specifically refers to an alkyl group that is substituted with one or more halides (halogens; e.g., fluorine, chlorine, bromine, or iodine).
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • alkylamino specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like.
  • “alkyl” is used in one instance and a specific term such as“alkylalcohol” is used in another, it is not meant to imply that the term“alkyl” does not also refer to specific terms such as“alkylalcohol” and the like.
  • cycloalkyl refers to both unsubstituted and substituted cycloalkyl moieties
  • the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl”
  • a substituted alkoxy can be specifically referred to as, e.g, a“halogenated alkoxy”
  • a particular substituted alkenyl can be, e.g, an“alkenylalcohol,” and the like.
  • alkenyl refers to unsaturated, straight-chained, or branched hydrocarbon moieties containing a double bond.
  • C2- C 24 e.g., C2-C22, C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C 2 -C 8 , C 2 -C 6 , C2-C4 alkenyl groups are intended.
  • Alkenyl groups may contain more than one unsaturated bond.
  • Examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -methyl- 1-propenyl, 2-methyl- 1-propenyl, l-methyl-2-propenyl, 2 -m ethyl-2 - propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl- 1-butenyl, 2-methyl- 1- butenyl, 3 -methyl- 1-butenyl, 1-m ethyl-2 -butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,
  • 2-propenyl refers to a group having the structure -CEUCEh; 1-propenyl refers to a group with the structure-CEUCEl-CEE; and 2- propenyl refers to a group with the structure -CH2-CEUCH2.
  • Alkenyl substituents may be unsubstituted or substituted with one or more chemical moieties.
  • substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied.
  • alkynyl represents straight-chained or branched hydrocarbon moieties containing a triple bond.
  • C2-C24 e.g., C2- C22, C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C 2 -C 8 , C 2 -C 6 , C2-C4 alkynyl groups are intended.
  • Alkynyl groups may contain more than one unsaturated bond.
  • Examples include C2-C6-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2- butynyl, 3-butynyl, l-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3- m ethyl- 1-butynyl, l-methyl-2-butynyl, 1 -methyl-3 -butynyl, 2-methyl-3-butynyl, 1,1- dimethyl-2-propynyl, l-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- hexynyl, 3 -methyl- 1-pentynyl, 4-methyl- 1-pentynyl, l
  • Alkynyl substituents may be unsubstituted or substituted with one or more chemical moieties.
  • suitable substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.
  • aryl refers to groups that include a monovalent aromatic carbocyclic group of from 3 to 20 carbon atoms.
  • Aryl groups can include a single ring or multiple condensed rings.
  • aryl groups include C6-C10 aryl groups. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl.
  • the aryl group can be a phenyl, indanyl or naphthyl group.
  • heteroaryl is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus.
  • non heteroaryl which is included in the term“aryl,” defines a group that contains an aromatic group that does not contain a heteroatom.
  • the aryl or heteroaryl substituents may be unsubstituted or substituted with one or more chemical moieties.
  • substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, cycloalkyl, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein.
  • the term“biaryl” is a specific type of aryl group and is included in the definition of aryl. Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in
  • naphthalene or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
  • heterocycloalkyl is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein.
  • cycloalkenyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one double bound, i.e.,
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
  • the term“heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term“cycloalkenyl,” where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein.
  • cyclic group is used herein to refer to either aryl groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups), or both. Cyclic groups have one or more ring systems that can be substituted or unsubstituted. A cyclic group can contain one or more aryl groups, one or more non-aryl groups, or one or more aryl groups and one or more non-aryl groups.
  • acyl as used herein is represented by the formula -C(0)Z 1 where Z 1 can be a hydrogen, hydroxyl, alkoxy, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • Z 1 can be a hydrogen, hydroxyl, alkoxy, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • alkoxy refers to a group of the formula Z'-O-, where Z 1 is unsubstituted or substituted alkyl as defined above. Unless otherwise specified, alkoxy groups wherein Z 1 is a C1-C24 (e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4) alkyl group are intended.
  • C1-C24 e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4 alkyl group are intended.
  • Examples include methoxy, ethoxy, propoxy, 1 -methyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy, 1,1 -dimethyl- ethoxy, pentoxy, 1-methyl-butyloxy, 2-methyl-butoxy, 3-methyl-butoxy, 2, 2-di -methyl - propoxy, 1-ethyl-propoxy, hexoxy, 1, 1 -dimethyl -propoxy, 1,2-dimethyl -propoxy, 1 -methyl - pentoxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 4-methyl-penoxy, 1, 1 -dimethyl -butoxy, 1,2- dimethyl -butoxy, 1,3 -dimethyl -butoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl-butoxy, 3,3- dimethyl -butoxy, 1 -ethyl -butoxy, 2-ethylbutoxy, 1, 1, 2-trimethyl -propoxy, 1,2,2-trimethyl- propoxy,
  • aldehyde as used herein is represented by the formula— C(0)H.
  • amine or“amino” as used herein are represented by the formula— NZ X Z 2 , where Z 1 and Z 2 can each be substitution group as described herein, such as hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.“Amido” is — C(0)NZ 1 Z 2 .
  • esters as used herein is represented by the formula— OC(0)Z 1 or — C(0)OZ 1 , where Z 1 can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • ether as used herein is represented by the formula Z l OZ 2 , where Z 1 and Z 2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • ketone as used herein is represented by the formula Z 1 C(0)Z 2 , where Z 1 and Z 2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • halide or“halogen” or“halo” as used herein refers to fluorine, chlorine, bromine, and iodine.
  • hydroxyl as used herein is represented by the formula— OH.
  • silica as used herein is represented by the formula— SiZ 1 Z 2 Z 3 , where Z 1 , Z 2 , and Z 3 can be, independently, hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula— S(0) 2 Z', where Z 1 can be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
  • Me refers to a methyl group
  • OMe refers to a methoxy group
  • i- Pr refers to an isopropyl group.
  • R 1 ,”“R 2 ,”“R 3 ,”“R n ,” etc., where n is some integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an amine group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • the amino group can be incorporated within the backbone of the alkyl group.
  • the amino group can be attached to the backbone of the alkyl group.
  • the nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
  • a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible stereoisomer or mixture of stereoisomer (e.g., each enantiomer, each diastereomer, each meso compound, a racemic mixture, or scalemic mixture).
  • the agonist can have an EC50 of 800 nM or less at estrogen receptor beta (ERP) (e.g., 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4.5 nM or less, 4 nM or less, 3.5 nM or less, 3 nM or less, 2.5 nM or less, 2 nM or less, 1.5
  • ERP estrogen receptor beta
  • the agonist can have an EC50 of 1 pM or more at ERp (e.g., 0.1 nM or more, 0.2 nM or more, 0.3 nM or more, 0.4 nM or more, 0.5 nM or more, 0.6 nM or more, 0.7 nM or more, 0.8 nM or more, 0.9 nM or more, 1 nM or more, 1.5 nM or more, 2 nM or more, 2.5 nM or more, 3 nM or more, 3.5 nM or more, 4 nM or more, 4.5 nM or more, 5 nM or more, 6 nM or more, 7 nM or more, 8 nM or more, 9 nM or more, 10 nM or more, 20 nM or more, 30 nM or more, 40 nM or more, 50 nM or more, 60 nM or more, 70 nM or more, 80 nM or more, 90 nM
  • the EC50 of the agonist at ERP can range from any of the minimum values described above to any of the maximum values described above.
  • the compounds disclosed herein can have an EC50 of from 1 pM to 800 nM at ERP (e.g., from 1 pM to 400 nM, from 400 nM to 800 nM, from 1 pM to 300 nM, from 1 pM to 200 nM, from 1 pM to 100 nM, from 1 pM to 50 nM, from 1 pM to 20 nM, from 1 pM to 10 nM, from 1 pM to 6 nM, from 1 pM to 5 nM, from 1 pM to 2 nM, from 1 pM to 1 nM, from 1 pM to 0.7 nM, from 1 pM to 0.5 nM, from 1 pM to 0.2 pM, or from 1 pM to 0.1 nM).
  • the agonist can be a selective ERp agonist.
  • a selective ERp agonist is a compound that has a lower EC50 at ERp than at estrogen receptor a (ERa).
  • the selectivity of the agonists can, in some examples, be expressed as an ERP-to- ERa agonist ratio, which is the EC50 of the compound at ERa divided by the EC50 of the compound at ERp.
  • the agonists can have an ERP-to-ERa agonist ratio of 8 or more (e.g., 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 150 or more, 200 or more, 250 or more, 300 or more, 350 or more, 400 or more, 450 or more, 500 or more, 600 or more, 700 or more, 800 or more, 900 or more, 1000 or more, 1100 or more, 1200 or more, 1300 or more, 1400 or more, 1500 or more, 2000 or more, 2500 or more).
  • 8 or more e.g., 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 150 or more, 200 or more, 250 or more, 300 or more, 350 or more, 400 or more, 450 or more, 500 or more, 600 or more, 700 or more, 800 or more, 900 or more,
  • the agonists can have an ERb-to-ERa agonist ratio of 3000 or less (e.g., 2500 or less, 2000 or less, 1500 or less, 1400 or less, 1300 or less, 1200 or less, 1100 or less, 1000 or less, 900 or less, 800 or less, 700 or less, 600 or less, 500 or less, 450 or less, 400 or less, 350 or less, 300 or less, 250 or less, 200 or less, 150 or less, 100 or less, 90 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less, 30 or less, 20 or less, or 10 or less).
  • 3000 or less e.g., 2500 or less, 2000 or less, 1500 or less, 1400 or less, 1300 or less, 1200 or less, 1100 or less, 1000 or less, 900 or less, 800 or less, 700 or less, 600 or less, 500 or less, 450 or less, 400 or less, 350 or less, 300 or less, 250 or less, 200 or less, 150 or
  • the ERb-to-ERa agonist ratio of the compounds at ERb can range from any of the minimum values described above to any of the maximum values described above.
  • the compounds can have an ERb-to-ERa agonist ratio of from 8 to 3000 (e.g., from 8 to 1500, from 1500 to 3000, from 400 to 3000, from 500 to 3000, from 600 to 3000, from 700 to 3000, from 800 to 3000, from 900 to 3000, from 1000 to 3000, or from 2000 to 3000).
  • ERIb agonists are known in the art, and described for example in Mohler, M. L., et al“Estrogen Receptor b Selective Nonsteroidal Estrogens: Seeking Clinical Indications” Expert Opin. Ther. Patents (2010) 20(4): 507-534, which is incorporated herein by reference.
  • the agonist can be a hydroxy-biphenyl-carbaldehyde oxime derivative. Examples of such agonists are described, for example, in U.S. Patent No.
  • the agonist can be defined by Formula I below
  • R 1 and R 2 are each, independently, H, halogen, CN, substituted or unsubstituted phenyl, or substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl);
  • R 3 , R 4 , R 5 and R 6 are each independently, H, OH, halogen, CN, substituted or unsubstituted phenyl, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted Ci-Ce alkyl), or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy);
  • R 8 are each, independently H, -C(0)R 9 , or substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl); and
  • R 9 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl);
  • R 8 is, in each case, H.
  • the agonist can be one of the compounds shown below.
  • the agonist can be a naphthyl-linked carbaldehyde oxime derivative. Examples of such agonists are described, for example, in U.S. Patent No.
  • the agonist can be defined by Formula II below
  • R 1 is hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy);
  • R 2 and R 3 together, form a fused aryl or heteroaryl ring
  • R 4 is hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy);
  • R 5 are each, independently H, -C(0)R 6 , or substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl); and
  • R 6 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl);
  • R 5 is, in each case, H.
  • the agonist can be one of the compounds shown below.
  • the agonist can be an indole-linked carbaldehyde oxime derivative.
  • examples of such agonists are described, for example, in U.S. Patent No. 7,250,440 to Mewshaw et al. and International Publication No. WO 2005/018636 to Mewshaw et al., each of which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula III below
  • Ri is hydrogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl), halogen, CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C 1 -C 6 alkoxy) and R 2 IS hydrogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl), or substituted or unsubstituted phenyl; or Ri and R 2 together may form a 5-7 membered ring; and
  • R 3 , and R 4 are each, independently, H, OH, halogen, CN, substituted or unsubstituted phenyl, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl), or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C 1 -C 6 alkoxy);
  • the agonist can be one of the compounds shown below.
  • the agonist can be defined by Formula IV below
  • R 1 is, independently for each occurrence, H, -C(0)R 4 , or substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl); and
  • R 2 is hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C 6 alkoxy);
  • R 3 is hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C 6 alkoxy); and
  • R 4 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl);
  • R 1 is, in each case, H.
  • the agonist can be one of the compounds shown below.
  • the agonist can comprise 2,3-bis(4- hydroxyphenyl)propionitrile (DPN) or a derivative or analog thereof.
  • DPN 2,3-bis(4- hydroxyphenyl)propionitrile
  • the agonist can be a compound defined by Formula V below
  • the dashed line indicates a single bond or a double bond
  • R 1 is, independently for each occurrence, H, -C(0)R 6 , or substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl);
  • R 2 and R 3 are each, independently, H or CN;
  • R 4 and R 5 are each, independently, hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy); and
  • R 6 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl);
  • R 1 is, in each case, H.
  • the agonist can be a compound defined by the formula below wherein R 4 and R 5 are each, independently, hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy). In one embodiment, R 4 and R 5 are each, independently, hydrogen or methyl.
  • the agonist can be a compound defined by the formula below.
  • the agonist can be a compound defined by the formula below
  • R 4 is hydrogen or CN.
  • the agonist can be a sulfonamide.
  • Examples of such agonists are described, for example, in U.S. Patent Application Publication No. 20070021495 to Katzenellenbogen et al., which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula VI below
  • AR is an optionally substituted aryl group
  • R3 is an alkyl, alkenyl, alkynyl, benzyl, or phenyl group
  • Ri is a hydrogen, a halide, a hydroxy, thiol, an alkyl, alkenyl, alkynyl, benzyl, phenyl alkoxy, thioalkoxy, or aryloxy group;
  • Xi— X4 independently of one another, are selected from the group consisting of hydrogens, halogens, alkyl groups, alkoxy groups,— CO— R groups,— SR groups, cyano groups, nitro groups, hydroxy groups, alkoxy groups, thiol groups, and thioalkoxy groups, where R is H, or an alkyl group, wherein R3 can be linked with X3, or X4 to form a 5, 6 or 7- member ring which may be an aromatic ring, or may contain one or two double bonds and wherein the ring optionally contains one or two additional heteroatoms wherein all alkyl, alkenyl, alkynyl, aryl, benzyl and phenyl groups are optional substituted and wherein optional substitution means substitution with one or more halogens, cyano groups, nitro groups, hydroxy groups, alkoxy groups, thiol groups, thioalkoxy groups, aryloxy groups, N(R)' 2 groups, CON(R
  • the agonist can be defined by the formula below
  • R is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl, such as -CH , -CH 2 CH 2 CH , -CH 2 CH 2 CH 2 CH , -CH(CH )(CH 2 CH ), - CH(CH )(CH 2 CH 2 CH ), or -CH 2 CH 2 CF ).
  • substituted or unsubstituted alkyl e.g., substituted or unsubstituted C1-C6 alkyl, such as -CH , -CH 2 CH 2 CH , -CH 2 CH 2 CH 2 CH , -CH(CH )(CH 2 CH ), - CH(CH )(CH 2 CH 2 CH ), or -CH 2 CH 2 CF ).
  • the agonist can comprise a monocycle-linked bis-phenyl estrogenic agonist.
  • Examples of such agonists are described, for example, in International Publication No. WO 2000/019994 to Katzenellenbogen et al., which is hereby incorporated by reference in its entirety.
  • the agonist can comprise a thiophene-based agonist.
  • the agonist can be defined by Formula VII below
  • R 1 is phenyl optionally substituted with 1-4 Y groups
  • R 2 is phenyl optionally substituted with 1-4 Y groups, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, haloalkenyl of 2-7 carbon atoms, or haloalkynyl of 2-7 carbon atoms;
  • R 3 is hydrogen, phenyl optionally substituted with 1-4 Y groups, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkoxy carbonyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, haloalkenyl of 2-7 carbon atoms, or haloalkynyl of 2-7 carbon atoms;
  • Y is— OH,— OR 4 , halogen,— CN,— CO2H,— CO2R 4 , alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, or— COR 4 ;
  • R 4 and R 5 are each, independently, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
  • R 2 or R 3 is phenyl or phenyl substituted with 1-4 Y groups
  • the agonist can be a compound defined by the formula below
  • Ris hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy).
  • R is hydrogen or halogen (e.g., F or Cl).
  • the agonist can comprise a cycloalkane-linked biphenyl. Examples of such agonists are described, for example, in U.S. Patent Application
  • the agonist can be defined by Formula VIII below
  • n is an integer selected from the group consisting of 3, 4, 5 and 6;
  • Ri is selected from the group consisting of hydrogen, Ci-Cx straight chained or branched alkyl, Ci-Cs straight chained or branched alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclyl, sulphonyl, Ci-Cx straight chained or branched perhaloalkyl,
  • R 3 groups are optionally bound together to form a substituted or unsubstituted C 3 - C 9 cycloalkyl or C 3 -C 9 heteroalicyclyl;
  • any bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;
  • R4 a and R4 b are optionally bound together to form an aryl, heteroaryl, or heteroalicyclyl;
  • Z is oxygen or sulfur
  • Rfdon Rs a , and R 3 ⁇ 4 are separately selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalicyclyl.
  • the agonist can comprise a spiro indene-indene agonist.
  • a spiro indene-indene agonist examples are described, for example, in International Publication No. WO 2002/091993 to Blizzard et ah, which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula IX below
  • R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently selected from the the group consisting of R a , OR a , OC0 2 R a , NR a R a , C0 2 R a , CN, Cl, F and Br;
  • R 11 , R 12 , R 13 and R 14 are each independently selected from the group consisting of H, R b , OR b , OC0 2 R b , NR a R b , C0 2 R b , F, Cl, CN, Br;
  • R 5 is selected from the group consisting of H, F and Ci- 6 alkyl
  • R a is selected from the group consisting of H, Ci- 6 alkyl and Ci- 6 acyl;
  • R b is selected from the group consisting of C 2 -7alkyl and C 2 -7acyl, wherein said alkyl and acyl groups may be optionally substituted with an R c group;
  • R c is selected from the group consisting of OR d and NR d R e ,
  • R d and R e are each independently selected from the group consisting of H and Ci-
  • R d and R e can be taken together with the nitrogen atom to which they are attached to form a 4-8 membered ring, wherein said ring is optionally interrupted by one of O, NH, NCFF and S and is optionally substituted with one, two, three or four Ci- 2 alkyl groups, or one or two R f groups;
  • R f is selected from the group consisting of CH 2 OH and CH 2 CH 2 OH;
  • the agonist can be a phenyl bicyclic agonist, such as an indenone agonist, an indene agonist, a benzofuran agonist, a benzimidazole agonist, a benzthiazole agonist, a benzoxazole agonist, a benzisoxazole agonist, an indazole agonist, an indole agonist, or a benzisothiazole agonist.
  • a phenyl bicyclic agonist such as an indenone agonist, an indene agonist, a benzofuran agonist, a benzimidazole agonist, a benzthiazole agonist, a benzoxazole agonist, a benzisoxazole agonist, an indazole agonist, an indole agonist, or a benzisothiazole agonist.
  • the agonist can comprise an indenone agonist.
  • indenone agonists are described, for example, in U.S. Patent No. 6,903,238 to McDevitt et ak, which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula X below
  • Ri is hydrogen, hydroxyl, halogen, trifluoroalkyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6 carbon atoms, sulfonoalkyl of 1-6 carbon atoms,— CN,— NO?,— CHFCN,— CFiCN, aryl of 6-10 carbon atoms,— NR4R5,— NCOR 4 ,— SR 4 ,— SOR 4 ,— SO2R4, or a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, cycl
  • R 2 is hydrogen, hydroxyl, alkyl of 1-6 carbon atoms, halogen, phenyl substituted with Ri, alkylthio of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, amino, aminoalkyl of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or alkenyl of 2-7 carbon atoms;
  • R3 is hydrogen, halogen, hydroxyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms;
  • R 4 and R5 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6- 10 carbon atoms;
  • the agonist can be any organic compound that can be used in certain embodiments.
  • the agonist can be any organic compound that can be used in certain embodiments.
  • R 1 is halogen (e.g., Br)
  • R 2 is hydrogen
  • R 3 is hydroxy
  • R 4 is hydrogen
  • the agonist can be any organic compound that can be used in certain embodiments.
  • the agonist can be any organic compound that can be used in certain embodiments.
  • R 1 is halogen (e.g., Br), R 2 is hydroxy, R 3 is hydrogen, and R 4 is hydrogen.
  • the agonist can be wherein R 1 is methyl, R 2 is hydroxy, R 3 is hydrogen, and R 4 is hydroxy.
  • the agonist can comprise an indene agonist.
  • indene agonists are described, for example, in International Publication No. WO 2008/043567 to Jemstedt et al. and U.S. Patent Application Publication No. 2009/0326018 to Jernstedt et ah, each of which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula XI below
  • R 1 and R 2 are independently selected from the group consisting of hydrogen, OR A , Ci- 6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8cycloalkyl Ci- 6 alkyl, C 6-10 aryl, C 6 - l oaryl Ci- 6 alkyl, halogen, halo Ci- 6 alkyl, dihalo Ci- 6 alkyl and trihalo Ci- 6 alkyl; or R 1 and R 2 taken together with the carbon atom to which they are attached form a double bond portion of C2-6 alkenyl group;
  • R A is selected from the group consisting of hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, C 2 - 6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl Ci-6 alkyl, C6-10 aryl and C6-10 aryl Ci-6 alkyl;
  • R 3 is selected from the group consisting of hydrogen, Ci- 6 alkyl, C3-8cycloalkyl and — C(0)Ci-4 alkyl;
  • R 4 , R 5 , R 6 and R 7 are the same or are different and each is selected from the group consisting of hydrogen, OR A , halogen, cyano, nitro, Ci- 6 alkyl, C2-6alkenyl, C2-6 alkynyl, halo Ci- 6 alkyl, dihalo Ci- 6 alkyl and trihalo Ci- 6 alkyl;
  • R 8 is selected from the group consisting of C3-8 cycloalkyl, C3-8 cycloalkyl Ci- 6 alkyl, phenyl, benzyl and C 5-10 heterocyclyl wherein said phenyl, benzyl or C 5-10 heterocyclyl group can either be unsubstituted or substituted with 1-3 substituents and each substituent is selected from the group consisting of OR A , halogen, cyano, nitro, Ci- 6 alkyl, C2-6 alkenyl, C2-6alkynyl, halo C 1.4 alkyl, dihalo Ci- 6 alkyl, trihalo Ci- 6 alkyl and C(0)Ci ⁇ alkyl; R 10 is OR a ; and
  • R 9 , R 11 and R 12 are the same or are different and each is selected from the group consisting of hydrogen, OR A , halogen, cyano, nitro, C i-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C(0)H, C(0)Ci- 6 alkyl, halo C i-6 alkyl, dihalo Ci-6 alkyl and trihalo Ci-6 alkyl;
  • the agonist can be the compound shown below.
  • the agonist can comprise a benzofuran agonist.
  • a benzofuran agonist examples are described, for example, in U.S. Patent No. 6,774,248 to Miller et ah, which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula XII below
  • A is alkyl of 1-6 carbon atoms, halogen, trifluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms,— CO2H,— NFF, or— OP;
  • A' is— OP,— CO2P, halogen, or hydroxyalkyl
  • P is hydrogen, alkyl of 1-6 carbon atoms, or phenyl
  • R and R' are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2- 7 carbon atoms, halogen,— OP,— SP,— SOP,— SO2P,— SCN, trifluoroalkyl of 1-6 carbon atoms,— CF2CF3, trifluoroalkoxy of 1-6 carbon atoms,— NO2,— NFF,— NHOP, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl group, -alkyl - SP, -alkyl-SOP, -alkyl-S0 2 P,— CN, -alkyl-CN, -alkenyl-CN, -alkylSCN,— CHFCN,— CF2CN, -alkenyl-N0 2 , haloalkyl of 1-6 carbon atoms, dihaloalkenyl of 2-7 carbon atoms, —COP,— CO
  • X and Y are each, independently, hydrogen, alkyl of 1-6 carbon atoms, halogen,— NO2,— CN, trifluoroalkyl of 1-6 carbon atoms,— OP, hydroxyalkyl of 1-6 carbon atoms,
  • the agonist can be the compound shown below.
  • the agonist can comprise a benzimidazole agonist, a benzthiazole agonist, or a benzoxazole agonist.
  • a benzimidazole agonist a benzthiazole agonist
  • a benzoxazole agonist examples of such agonists are described, for example, in International Publication No. WO 2002/046168 to Barlaam et al.,
  • the agonist can be defined by Formula XIII below
  • R a is H, Ci- 6 alkyl, Ci.3haloalkyl, phenyl or benzyl;
  • n 0, 1, 2 or 3; or a pharmaceutically acceptable salt or ester thereof.
  • the agonist can be defined by Formula XIV below
  • X is O or S
  • R a is H, Ci- 6 alkyl, C1-3 haloalkyl, phenyl or benzyl; or
  • the agonist can be defined by Formula XV below
  • X is O or S
  • R 4 is H or— NR a R b ;
  • R 5 is H or— NR a R b ; wherein R 4 and R 5 are not both H;
  • R a is H, Ci- 6 alkyl, Ci-3haloalkyl, phenyl or benzyl;
  • the agonist can be the compound shown below.
  • the agonist can comprise a naphthyl-benzoxazole agonist or a benzoxazole agonist.
  • a naphthyl-benzoxazole agonist or a benzoxazole agonist.
  • Examples of such agonists are described, for example, in U.S. Patent No. 6,960,607 to Malamas et al. and U.S. Patent No. 6,794,403 to Malamas et ah, each of which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula XVI below
  • A is one of the groups shown below
  • R 1 , R 3 , and R 4 are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms,—COR 5 ,— C0 2 R 5 ,— N0 2 , CONR 5 R 6 , NR 5 R 6 or N(R 5 )COR 6 ;
  • R 2 is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, triflouroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6 carbon atoms, sulfonoalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, a 5 or 6-membered
  • heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S,— N0 2 ,— NR 5 R 5 ,— N(R 5 )COR 6 ,— CN,— CHFCN,— CF 2 CN, alkynyl of 2-7 carbon atoms, or alkenyl of 2-7 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluroalkyl, trifluoroalkoxy,— COR 5 ,— CO 2 R 5 ,— NO?, CONR5R5, NR5R5 or N(R5)CORe;
  • R 5 and R 6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, aryl of 6-10 carbon atoms,— CN,— CHFCN, or— CF 2 CN; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms,— COR 7 ,— C0 2 R 7 ,— NO?,
  • R 7 and R 8 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6- 10 carbon atoms;
  • X is O, S, or NR 9 ;
  • R 9 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, COR 5 , C0 2 R 5 , or S0 2 R 5 ;
  • the agonist can be defined by Formula XVII below
  • Ri is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, triflouroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6 carbon atoms, sulfonoalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S,— NO 2 ,— NR Rr,,— N(R 5 )COR 6 ,— CN,— CHFCN,— CF 2 CN, alkynyl of 2-7 carbon atoms, or alkenyl of 2-7 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl
  • R 2 and R 2a are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluoroalkyl, trifluoroalkoxy,— COR5,— CO2R5,— NO2, CONR5R5, NR5R5 or
  • R 3 , R 3a , and R 4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluoroalkyl, trifluoroalkoxy,— COR5,— CO2R5,— NO2, CONR5R5, NR5R5 or
  • R 5 , Rr are each, independently hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms;
  • X is O, S, or NR 7 ;
  • R 7 IS hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms,— COR 5 ,— CO2R5 or— SO2R5; or a pharmaceutically acceptable salt or ester thereof.
  • the agonist can be one of the compounds shown below.
  • the agonist can comprise a benzimidazole agonist.
  • a benzimidazole agonist examples are described, for example, in U.S. Patent Application Publication No. 2004/0002524 to Chesworth et af, which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula XVIII below
  • R 1 and R 2 are each independently selected from the group consisting of (Ci-
  • C6)alkylcarbonyl — CHO, cyano, thio; (Ci-C6)alkylthio; (Ci-C6)alkylsulfonyl; (Ci-
  • R 12 R 13 N(C I -C 6 ); R 12 R 13 N(Ci-C 6 )alkoxy; R 12 R 13 N(Ci-C 6 alkyl)S; N-morpholino(CH 2 ) n O; or
  • C6)alkenylcarbonylamino; or (Ci-C6)alkoxycarbonyloxy groups are each optionally further substituted by from 1 to 3 substituents independently selected from the group consisting of halogen, (C i-Ce)alkyl; (C 3 -C 8 )cycloalkyl; (C 4 -C 8 )cycloalkenyl; (Ci-C6)alkoxy, hydroxy, R 12 C0 2 , R 12 R 13 NCO, R 12 R 13 N;(Ci-C 6 )alkylcarbonyl,— CHO, cyano, thio; R 12 S0 2 (Ci- C 6 )alkyl; R 12 C0 2 (Ci-C 6 )alkyl; R 12 R 13 NCO(Ci-C 6 )alkyl; R 12 CO(Ci-C 6 )alkyl; R 12 S0 2 (Ci- C 6 )alkoxy; R 12 C0 2 (Ci-C 6 )
  • R 1 and R 2 are each independently a group of the Formula A:
  • R 7 , R 8 , R 10 and R 11 are each independently hydrogen; hydroxy; (Ci-Ce) alkyl; (Ci- C 6 )alkoxy; or halogen;
  • R 9 is hydroxy; (Ci-Ce) alkoxy; (Ci-C 6 )alkoxycarbonyloxy; (Ci- C 6 )alkylcarbonyloxy; (C3-C8)cycloalkoxy; (C4-C8)cycloalkenyloxy; or (C6-C12) aryloxy; and
  • R 3 , R 4 , R 5 and R 6 are each independently hydrogen, hydroxy; (Ci-Ce)alkyl; (Ci- C 6 )alkoxy, or halogen;
  • the agonist can be one of the compounds below.
  • the agonist can be an indazole agonist, such as the compound shown below.
  • the agonist can comprise an indole agonist.
  • indole agonist examples are described, for example, in Japanese Patent Application Publication No. JP2001122855 to Fujii et al., and U.S. Patent Application Publication No. 2003/0220377 to Chesworth, each of which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula XIX below
  • R 1 and R 2 are each independently selected from the group consisting of (Ci- C 6 )alkyl; phenyl; (C2-C6)heteroaryl; (C3-C8)cycloalkyl; and (C4-C8)cycloalkenyl; wherein the (C i-C 6 )alkyl; phenyl; (C2-C6)heteroaryl; (C3-C8)cycloalkyl; or (C -Cs) cycloalkenyl groups of R 1 or R 2 are optionally substituted by from 1 to 3 substituents independently selected from the group consisting of halogen; (C i-C 6 )alkyl; (C3-C8)cycloalkyl; (C4- C 8 )cycloalkenyl; (Ci-C 6 )alkoxy; hydroxy; R 12 CO 2 , R 12 R 13 NCO, R 12 R 13 N; (Ci-C 6 ) alkylcarbonyl,— CHO,
  • R 1 and R 2 are each independently a group of the Formula A
  • R 8 , R 9 , R 11 and R 12 are each independently hydrogen; hydroxy; (Ci-
  • R 10 is hydrogen; hydroxy; (Ci-C 6 )alkoxy; (Ci-C 6 )alkoxycarbonyloxy; (Ci- C 6 )alkylcarbonyloxy; (C3-C8)cycloalkoxy; (C4-C8)cycloalkenyloxy; or (C 6 -Ci 2 ) aryloxy;
  • R 3 , R 4 , R 5 and R 6 are each independently hydrogen, hydroxy; (Ci-Ce)alkyl; (Ci- C 6 )alkoxy; or halogen; and
  • R 7 is H or (Ci-C3)alkyl
  • the agonist can be a compound shown below.
  • the agonist can comprise an indazole agonist, a
  • benzisoxazole agonist or a benzisothi azole agonist.
  • Examples of such agonists are described, for example, in International Publication No. WO 2006/040351 to Rondot et al., which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula XX below
  • R 2 and R 3 are each independently hydrogen or a hydroxyl, halogen, nitro, cyano, (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (Ci-C 6 )alkoxy, trifluoromethyl,— NR-Rx,— CONR 7 R 8 ,— COR 9 or— CO 2 R 9 group;
  • R 2 can also be a phenyl or a saturated or unsaturated heterocycle, wherein the phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C 3 )alkyl, a (Ci- C 3 )alkoxy, a trifluoromethyl and a saturated heterocyclic radical;
  • X is O, S, SO, S0 2 or NR 4 ;
  • R 4 IS hydrogen or a (Ci-C 6 )alkyl, (C 3 -C 6 )cycloalkyl, phenyl, phenyl(Ci-C 3 )alkyl, (Ci-C 3 )alkyl substituted by a saturated heterocyclic radical,— COR 7 ,— CO 2 R 7 or— SO 2 NR 7 R 8 group, wherein the phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C 3 )alkyl, a (Ci-C 3 )alkoxy, a trifluoromethyl, a phenyl(Ci-C 3 )alkyl and a phenyl(Ci- C 3 )alkoxy;
  • R 5 , Rs, R 7 and Rx are each independently hydrogen or a (Ci-C 6 )alkyl or (C 3 - C 6 )cycloalkyl group;
  • Jig is hydrogen, a (Ci-C 6 )alkyl, a phenyl or a saturated or unsaturated heterocyclic radical, wherein the phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C3)alkyl, a (Ci-C3)alkoxy, a trifluoromethyl and a saturated heterocyclic radical;
  • Rio and Rn are each independently hydrogen or a cyano, (Ci-C 6 )alkyl,— CO- phenyl,— CO(unsaturated heterocyclic radical) or— CONR7R8 group, wherein the phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C3)alkyl, a (Ci-C3)alkoxy and a
  • n 1 or 2;
  • A is a (C3-Ci5)cycloalkyl, a (C3-Ci5)cycloalkene, a phenyl or a naphthyl, wherein the cycloalkyl or the cycloalkene is unsubstituted or substituted by at least one (Ci-C 6 )alkyl, and wherein the phenyl or the naphthyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C3)alkyl, a (Ci-C3)alkoxy and a trifluoromethyl;
  • the agonist can be a compound shown below.
  • the agonist can comprise a bicyclic benzopyran agonist.
  • a bicyclic benzopyran agonist examples are described, for example, in International Publication No. WO 2003/074044 to Lugar et ah, which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula XXI below
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkoxy, halogen, or -CF3;
  • R 5 and R 6 are each independently hydrogen or substituted or unsubstituted alkyl; or a pharmaceutically salt thereof.
  • the agonist can be one of the compounds shown below.
  • the agonist can comprise a 3-alkyl-4-benzylchromane agonist.
  • Examples of such agonists are described, for example, in U.S. Patent Application Publication No. 2003/0069303 to Veeneman et ah, which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula XXII below
  • R 1 is (lC-4C)alkyl, (2C-4C)alkenyl or (2C-4C)alkynyl, and independently R 1 has a cis-orientation in relation to the exocyclic phenyl group at the 2-position of the skeleton;
  • R 4 is halogen, -CF3, OH or (lC-2C)alkyloxy; and R 2 , R 3 , and R 5 are independently H, halogen, -CF3, (lC-4C)alkyl, (2C-4C)alkenyl, or (2C-4C)alkynyl.
  • the agonist can comprise a compound described in
  • the agonist can be defined by Formula XXIII below
  • X is an asymmetric carbon atom having an S or R configuration
  • Ri is selected from the group consisting of H and OR4;
  • R 2 , R 3 , and R 4 are independently selected from the group consisting of H, and glycoside, glucuronide, acyl, phosphate, phosphonic acid, alkyl phosphonate, sulfate, Ci to C6 alkyl, C3 to C6 cycloalkyl, aryl, carbonate, and carbamate; each optionally substituted with from one to three groups selected from hydrogen, Ci to C6 alkyl, phenyl, benzyl, alkylphenyl, hydroxy, alkoxy, acyloxy, amino, carboxy and alkoxycarbonyl;
  • the agonist can be the compound defined below.
  • the agonist can comprise a compound described in
  • the agonist can be defined by Formula XXIV below
  • Ri, Re, R 9 , and Rio are independently selected from OH, H, halogen, cyano, amino, nitro, nitroso, C 1-5 alkyl, C 1-5 alkoxy, C 1-5 alkylcarbonyloxy; wherein each of said alkyl, alkoxy or alkylcarbonyloxy group is linear or branched;
  • R2 is selected from a branched C5 alkyl, a C6-20 alkyl, C6-20 alkenyl, C6-20 alkynyl or C6-20 alkenynyl, wherein each of said C6-20 alkyl, alkenyl, alkynyl or alkenynyl group is linear or branched;
  • R 3 , R 4, R 5 , Rs and R 7 are independently selected from OH, H, halogen, cyano, amino, nitro or nitroso;
  • Xi is selected from O, S;
  • X2 is selected from O, S or the two bonds are each separately formed with a hydrogen atom, wherein said naringenin derivative is not 8-geranylnaringenin.
  • the agonist can comprise a chroman-7-ol agonist.
  • a chroman-7-ol agonist examples are described, for example, in U.S. Patent No. 7,396,855 to Setchell et ah, and U.S. Patent No. 7,528,267 to Setchell et ah, each of which is hereby incorporated by reference in its entirety.
  • the agonist can comprise a tetrahydroisoquinoline agonist.
  • a tetrahydroisoquinoline agonist examples are described, for example, in U.S. Patent No. 6,686,351 to Bhagwat et ah, and U.S. Patent No. 7,256,201 to Barlaam et ah, each of which is hereby incorporated by reference in its entirety.
  • the agonist can comprise a quinazoline or quinazolinone agonist. Examples of such agonists are described, for example, in U.S. Patent No.
  • the agonist can comprise a 3-arylhydroxybenzoxazine agonist. Examples of such agonists are described, for example, in U.S. Patent No.
  • the agonist can comprise a 2-arylquinoline agonist.
  • the agonist can comprise a 2-phenylnaphthalene agonist.
  • Examples of such agonists are described, for example, in U.S. Patent No. 6,914,074, which is hereby incorporated by reference in its entirety.
  • the agonist can comprise a phenylnaphthalene agonist. Examples of such agonists are described, for example, in U.S. Patent Application
  • the agonist can comprise an isoquinolinone agonist.
  • the agonist can be defined by Formula XXV below
  • N forms a double bond with the cyclic carbon and X is OH or OCH2CH2-heterocycle in which the heterocycle is a 3-7 member saturated or unsaturated, substituted or unsubstituted heterocyclic ring;
  • R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, benzyl, -PI1-CF 3 , -Ph-CH 2 F, -Ph-CHF 2 , -Ph-CF 2 CF 3 , halogen, alkenyl, CN, NO 2 or OH;
  • R 1 is hydrogen, alkyl, or -COR
  • R" is hydrogen, alkyl, or -COR
  • R 4 and R 5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; Z is
  • Q is SO3H, CO2H, CO2R, NO2, tetrazole, SO2NH2 or SO2NHR;
  • n is an integer between 1-3;
  • n is an integer between 1-2;
  • p is an integer between 1-4;
  • Alkyl is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
  • the agonist can comprise a benzopyran agonist or a tetralin agonist. Examples of such agonists are described, for example, in U.S. Patent No.
  • the agonist can be defined by Formula XXVI below
  • X is CH or O
  • Ri, R 2 , and R 3 are independent hydrogen, halogen (e.g., F), substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C 1 -C 6 alkyl), -CF 3 , CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy).
  • the agonist can be defined by Formula XXVII below
  • G is -CH 2 -, -CH2CH2-, -CH 2 C(CH )2- or -0-;
  • R 1 is hydrogen, hydroxy or amino
  • R 2 is hydrogen or hydroxy
  • R 3 is hydrogen, hydroxy, Br, methyl, n-propyl, i-propyl, n-butyl, hydroxymethyl, methoxy, CH 3 CH(OH)-, acetyl, CH OCH 2 -, R 7 C(0)CH 2 CH 2 - Or R 8 CH 2 CH 2 CH 2 -; or R 2 and R 3 form a -CH 2 CH 2 -X-O- biradical, wherein the oxygen radical represents the R 2 end and the methylene radical represents the R 3 end;
  • R 4 is hydrogen, hydroxy, cyano, R 9 -CH 2 -, vinyl, 4-chlorophenyl, carboxy, aminocarbonyl or methoxycarbonyl;
  • R 5 is hydrogen, methyl, ethyl, R 10 -CH 2 -, CH 3 CH(OH)-, acetyl, carboxyl or methoxycarbonyl;
  • R 6 is hydrogen or fluoro
  • R 7 is amino, methylamino, dimethylamino or piperidin-l-yl
  • R 8 is bromo, hydroxy, dimethylamino or methoxy
  • R 9 is bromo, cyano, hydroxy, methoxy or azido
  • R 10 is bromo, hydroxy, cyano, methoxy or pyrrolidin-l-yl
  • R 1 , R 2 , R 3 and R 4 is hydroxy and at least three of R 1 , R 2 , R 3 , R 4 and R 5 are hydrogen;
  • the agonist can be defined by Formula XXVIII or Formula XXIX below
  • X is CH or O
  • R3 are independent hydrogen, halogen (e.g., F), substituted or unsubstituted alkyl
  • substituted or unsubstituted C1-C6 alkyl e.g., substituted or unsubstituted C1-C6 alkyl
  • -CF3, CN substituted or unsubstituted alkoxy
  • substituted or unsubstituted alkoxy e.g., substituted or unsubstituted C1-C6 alkoxy
  • the agonist can comprise a tri- or tetracyclic
  • the agonist can be defined by Formula XXX below
  • X is selected from the group consisting of: O, N— OR a , N— NR a R b and Ci- 6 alkylidene, wherein said alkylidene group is unsubstituted or substituted with a group selected from hydroxy, amino, 0(Ci- 4 alkyl), NH(Ci-4alkyl), or N(Ci-4alkyl)2;
  • Ci- 6 alkylidene group when taken together, form a Ci- 6 alkylidene group, wherein said alkylidene group is either unsubstituted or substituted with a group selected from the group consisting of hydroxy, 0(Ci- 4 alkyl), N(Ci- 4 alkyl) 2 , and phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci- 4 alkyl, OH, 0(Ci- 4 alkyl), NH 2 , NH(Ci- 4 alkyl), NH(Ci- 4 alkyl) 2 , halo, CN, N0 2 , C0 2 H, C0 2 (Ci- 4 alkyl), C(0)H, and C(0)(Ci- 4 alkyl);
  • R 4 and R 5 are each independently selected from the group consisting of hydrogen, hydroxy, amino, methyl, CF3, fluoro, chloro, and bromo;
  • R 7 is selected from the group consisting of hydrogen, OR b , NR b R c , fluoro, chloro, bromo, iodo, cyano, nitro, Ci- 6 alkyl, C 2-6 alenyl, CF3, and CBF 2 ;
  • R 8 and R 9 are each independently selected from the group consisting of hydrogen, fluoro, chloro, Ci- 6 alkyl, C2-6alkenyl, and C2-6alkynyl,
  • R 8 and R 9 when taken together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl ring,
  • R 10 is selected from the group consisting of hydrogen, Ci-ioalkyl, C2-ioalkenyl, C2- l oalkynyl, C3-6cycloalkyl, C4-6cycloalkenyl, (cycloalkyl)alkyl, (cycloalkyl)alkenyl,
  • cycloalkenyl alkyl, aryl, heteroaryl, arylalkyl and (heteroaryl)alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, (cycloalkyl)alkyl, (cycloalkyl)alkenyl,
  • R a is selected from the group consisting of hydrogen, Ci-ioalkyl, and phenyl, wherein said alkyl group can be optionally substituted with a group selected from hydroxy, amino, 0(Ci- 4 alkyl), NH(Ci-4alkyl), N(Ci- 4 alkyl) 2 , phenyl, or 1-5 fluoro, and wherein said phenyl groups can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci-4alkyl, OH, 0(Ci- 4 alkyl), NH2, NH(Ci-4alkyl), N(Ci- 4 alkyl) 2 , halo, CN, N0 2 , C0 2 H, C0 2 (Ci. 4 alkyl), C(0)H, and C(0)(Ci- 4 alkyl);
  • R b is selected from the group consisting of hydrogen, Ci-ioalkyl, benzyl and phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci-4alkyl, OH, 0(Ci- 4 alkyl), NH2, NH(Ci. 4 alkyl), N(Ci. 4 alkyl) 2 , halo, CN, N0 2 , C0 2 H, C0 2 (Ci. 4 alkyl), C(0)H, and C(0)(Ci- 4alkyl);
  • R c is selected from the group consisting of hydrogen, Ci-ioalkyl and phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci-4alkyl, OH, 0(Ci- 4 alkyl), NH 2 , NH(Ci. 4 alkyl), N(Ci. 4 alkyl) 2 , halo, CN, N0 2 , C0 2 H, C0 2 (Ci- 4 alkyl), C(0)H, and C(0)(Ci- 4alkyl);
  • R a and R c whether or not on the same atom, can be taken together with any attached and intervening atoms to form a 4-7 membered ring;
  • R e is selected from the group consisting of hydrogen, Ci- 6 alkyl, C 2-6 alkenyl, phenyl, and phenylalkyl, wherein said alkyl, alkenyl, or phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci- salkyl, OH, 0(Ci- 4 alkyl), NH 2 , NH(Ci- 4 alkyl), N(Ci- 4 alkyl) 2 , halo, CN, N0 2 , C0 2 H, C0 2 (Ci- 4 alkyl), C(0)H, and C(0)(Ci- 4 alkyl);
  • Y is selected from the group consisting of CR b R c , C 2-6 alkylene and C 2-6 alkenylene, wherein said alkylene and alkenylene linkers can be optionally interrupted by O, S, or NR C ; and
  • the agonist can comprise a pyranoflavonoid agonist.
  • the agonist can comprise a dibenzochromene agonist.
  • the agonist can comprise a 6H-chromeno[4,3-b]quinoline agonist.
  • 6H-chromeno[4,3-b]quinoline agonist examples are described, for example, in U.S. Patent Application Publication No. 2006/0052410 to Vu et al., which is hereby incorporated by reference in its entirety.
  • the agonist can comprise a tetracycle containing benzofuran. Examples of such agonists are described, for example, in U.S. Patent Application Publication No. 2006/0004087 to Miller et al., which is hereby incorporated by reference in its entirety.
  • the agonist can comprise WAY-358.
  • the agonist can comprise a cycloalkyl-substituted benzopyran.
  • a cycloalkyl-substituted benzopyran examples are described, for example, in International Publication No. WO 2004/094400 to Durst et al., which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula XXXI below
  • the agonist can comprise one or more of the following: (a) (2S, 3aS, 4R, 9bR)-4-(4-Hydroxy-phenyl)-2-methyl-l,2,3,3a,4,9b-hexahydro- cyclopenta[c]chromen-8-ol; (b) (2R, 3aR, 4S, 9bS)-4-(4-Hydroxy-phenyl)-2-methyl- l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (c) (2R, 3aR, 4S, 9bS)-2-tert-Butyl-4- (4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (d) (2S, 3aS, 4R, 9bR)-2-tert-Butyl-4-(4-hydroxy-phenyl)-2-ter
  • the agonist can comprise a steroidal derivative.
  • a steroidal derivative examples of such agonists are described, for example, in International Publication No. WO 2019/035061 to Micalizio et ah, which is hereby incorporated by reference in its entirety.
  • the agonist can be defined by Formula XXXIIA, XXXIIB, XXXIIC, or XXXTTD below
  • each R 2A and each R 4A is independently absent or, when present, selected from the group consisting of hydrogen, Ci-io-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, halogen, hydroxy, -OR ⁇ , -SR AY , -S(0) 2 NR Z1 R Z2 , -S(0) 2 R Z1 , -S(0)R Z1 , -NR Z1 R Z2 , -
  • R ⁇ is Ci- 6 -alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, -C(0)-Ci-io- alkyl, -C(0)-C 6 -io-aryl, -C(0)-heteroaryl, -C(0)-0-Ci-io-alkyl, -C(0)-0-C 6 -io-aryl, -C(O)- O-heteroaryl, -C(0)-NR Z1 R Z2 , -S(0)2R Z1 , C6-io-aryl, or 5- to 10-membered heteroaryl, wherein R AY is hydrogen, Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, - C(0)-Ci- 10-alkyl, -C(0)-C 6 -io-aryl, -C
  • each R 3A is independently absent or, when present, selected from the group consisting of hydrogen, Ci-io-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, halogen, -O ⁇ , -SR AY , - S(0) 2 NR Z1 R Z2 , -S(0) 2 R z 1 , -S(0)R Z1 , -NR Z1 R Z2 , -N(R Z1 )C(0)R Z2 , -N(R Z1 )S(0) 2 R Z2 , Ce-io- aryl, and 5- to 10-membered heteroaryl;
  • R 6A is selected from the group consisting of hydrogen, Ci-io-alkyl, C2-io-alkenyl, C2- 10- alkynyl, Ci-10-haloalkyl, halogen, oxygen, boronic acid, boronic acid ester, -OR BX , - SR by , - S(0) 2 NR Z1 R Z2 , -S(0) 2 R z 1 , -S(0)R Z1 , -NR Z1 R Z2 , -N(R Z1 )C(0)R Z2 , - N(R Z1 )S(0)2R Z2 , C6-io-aryl, 5- to 10-membered heteroaryl, C6-io-aryl-Ci-6-alkyl, C6-io-aryl- C2-6-alkenyl, and C6-io-aryl-C2-6- alkynyl,
  • R BX is Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, -C(0)-Ci-io- alkyl, -C(0)-C 6 -io-aryl, -C(0)-heteroaryl, C6-io-aryl, or 5- to 10-membered heteroaryl,
  • R BY is hydrogen, Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-10-haloalkyl, - C(0)-Ci-io-alkyl, -C(0)-C 6 -io-aryl, -C(0)-heteroaryl, C6-io-aryl, or 5- to 10-membered heteroaryl;
  • R UA is selected from the group consisting of hydrogen, oxygen, and OR cx , wherein R cx is Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, -C(0)-Ci-io- alkyl, -C(0)-C 6 -io-aryl, -C(0)-heteroaryl, C6-io-aryl, or 5- to 10-membered heteroaryl;
  • R 13A is selected from the group consisting of Ci- 6 -alkyl and C 6 -io-aryl-Ci- 6 -alkyl, wherein the C 6 -io-aryl is optionally substituted one or more halogen, Ci- 6 -alkyl, C1-6- haloalkyl, or Ci-6- alkoxy;
  • each R 16A is independently selected from the group consisting of hydrogen, hydroxy,
  • R DX is Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, -C(0)-Ci-io- alkyl, -C(0)-C 6 -io-aryl, -C(0)-heteroaryl, C6-io-aryl, or 5- to 10-membered heteroaryl
  • R DY is hydrogen, Ci- 6 -alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, -C(0)-Ci- 10-alkyl, -C(0)-C 6 -io-aryl, -C(0)-heteroaryl, C 6 -io-aryl, or 5- to 10-membered heteroaryl
  • each R 17A is independently selected from the group consisting of hydrogen, Ci-io- alkyl, C2-io-alkenyl, C2-io-alken
  • each dotted line independently represents a single bond or a double bond
  • the A ring is saturated, partially unsaturated, or completely unsaturated; and the B ring is saturated, partially unsaturated, or completely unsaturated;
  • any C 6 -io-aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, Ci- 6 -alkyl, Ci- 6 -haloalkyl, or Ci- 6 -alkoxy.
  • the agonist can be the compound defined below.
  • the agonist can comprise a 4-cycloheptylphenol, such as the compound shown below.
  • the agonist can comprise one of the compounds shown below.
  • the agonist can comprise a polyhydroxyphthalazinone.
  • the agonist can be a compound defined by Formula XXXIII below
  • R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, hydroxy, C 1-3 alkoxy or halogen;
  • R 5 is hydrogen, C 1-4 alkyl, C 1-4 halogenated alkyl, phenyl or cyano;
  • R 6 is hydrogen or halogen.
  • the halogen can be fluorine, chlorine or bromine.
  • R 1 , R 2 , and R 3 are hydroxy, R 4 and R 6 are hydrogen; and R 5 is hydrogen, C1-4 alkyl, C1-4 halogenated alkyl, phenyl or cyano.
  • R 1 , R 2 , and R 3 are hydroxy, R 4 and R 6 are hydrogen; and R 5 is chlorine or bromine.
  • R 1 , R 2 , and R 3 are hydroxy; R 4 is hydrogen or halogen; R 5 is hydrogen; R 6 is chlorine or bromine.
  • the agonist can comprise the compound below.
  • the agonist can comprise an isoflavone such as genistein, the structure of which is shown below.
  • the agonist can comprise one of the compounds shown below.
  • Non-Alcoholic Steatohepatitis is increasingly recognized as the most prevalent chronic liver disease in the world and an important precedent condition to hepatomatlar carcinoma (J. Gastroenterol. (2016) 53:362-376). With effective hepatitis B and C treatment and vaccination programs, respectively, largely in place, NASH mediated HCC is expected to soon overtake all other known causes of HCC (Cell. Metab. 2019 Jan 8;29(1): 18-26). NASH prevalence is thought to approach 40% of obese adults, driving up overall incidence in lock step with a growing obesity epidemic, and represents one of the largest unmet medical needs in medicine.
  • fatty liver disease displays marked sexual dimorphism such that rates of disease are higher in men than women, even when controlled for known risk factors (Adv Ther. 2017 Jun;34(6): 1291-1326.). This dimorphism suggests an important role for sex hormone signaling such that male hormones could be reasonably hypothesized to support NASH development, and conversely, female hormones expected to play a protective role.
  • exogenous estrogen administration can mitigate fat accumulation and adverse metabolic changes associated with high fat diet (FASEB J. 2017 Jan;31(l):266-281.; Mol Cell Endocrinol.
  • Therapeutic administration of steroidal endogenous estrogen preparations are associated with a number of limitations including but not limited to; exceedingly poor drug like properties, metabolic interconversion to other unwanted hormones, and unwanted severe estrogenic side-effects.
  • administration of a potent exogenous estrogen is accompanied with the fear of stimulating nascent breast cancer in a postmenopausal female NASH patient as was, with acknowledged controversy, shown to be a problem by the women’s health initiative (J Steroid Biochem Mol Biol. 2014 Jul; 142:4-11.).
  • exogenous estrogen administration is associated with severe risk of deep- vein thrombosis, as was shown when DES was widely given as a prostate cancer therapeutic (Urology. 2001 Aug;58(2 Suppl 1): 108-13.).
  • Estrogen pharmacology was further advanced with the characterization of an additional, highly related, ERP isoform that displayed differential tissue distribution and biology as compared to ERa, the originally described receptor for endogenous estrogens (Proc Natl Acad Sci USA 93:5925-5930). As ERp biology became increasingly well characterized, it was accompanied with considerable interest in the development of therapeutic estrogens that selectively target ERp over ERa as well as other closely related nuclear hormone receptors (Expert Opin Ther Pat. 2010 Apr;20(4): 507-34.).
  • One such ligand, Compound 1 is a carborane based highly ERP selective SERM.
  • Compound 1 could provide anti-NASH efficacy through combined anti-metabolic disease, antisteatotic, and anti-fibrotic effects.
  • Compound 1 was administered once daily as two dose levels by oral gavage to male STAM model mice (Cell Metab. 2019 Jan 8;29(1): 18-26, slide #2).
  • STAM mice are given pharmacologic beta-cell dysfunction to mimic Type 1 Diabetes and then given a 67% fat diet to recapitulate NASH progression. Mice treated during the steatosis phase for 7 weeks tolerated both dose levels very well.
  • Compound 1 (or other carborane based or non- carborane-based SERMS) could be broadly useful in a number of fibrotic diseases including but not limited to; IPF, Calcineurin-induced renal fibrosis, Renal fibrosis NOS, Cardiac fibrosis associated with chronic heart failure (CHF), Fibrosis associated with Post-MI cardiac remodeling, Dupuytren's contracture, Fibrosis associated with RA, Liver fibrosis (viral, alcoholic, unknown origin), Peyronie's disease, Keloid or other scarring (post- surgical, etc.).
  • IPF Calcineurin-induced renal fibrosis
  • Renal fibrosis NOS Cardiac fibrosis associated with chronic heart failure (CHF)
  • CHF chronic heart failure
  • Fibrosis associated with Post-MI cardiac remodeling Dupuytren's contracture
  • Fibrosis associated with RA Liver fibrosis (viral, alcoholic, unknown origin), Peyroni
  • Example fibrotic conditions that can be treated or prevented using E ⁇ Ib agonists include, but are not limited to, a fibrotic condition of the lung, liver, heart, vasculature, kidney, skin, gastrointestinal tract, bone marrow, or a combination thereof. Each of these conditions is described in more detail herein.
  • Fibrosis of the lung is characterized by the formation of scar tissue within the lungs, which results in a decreased function. Pulmonary fibrosis is associated with shortness of breath, which progresses to discomfort in the chest weakness and fatigue, and ultimately to loss of appetite and rapid weight-loss. Approximately 500,000 people in the U.S. and 5 million worldwide suffer from pulmonary fibrosis, and 40,000 people in the Ei.S. die annually from the disease. Pulmonary fibrosis has a number of causes, including radiation therapy, but can also be due to smoking or hereditary factors (Meltzer, E B et al. (2008) Orphanet J. Rare Dis. 3:8).
  • Pulmonary fibrosis can occur as a secondary effect in disease processes such as asbestosis and silicosis, and is known to be more prevalent in certain occupations such as coal miner, ship workers and sand blasters where exposure to environmental pollutants is an occupational hazard (Green, F H et al. (2007) Toxicol Pathol. 35:f36-47).
  • Other factors that contribute to pulmonary fibrosis include cigarette smoking, and autoimmune connective tissue disorders, like rheumatoid arthritis, scleroderma and systemic lupus erythematosus (SLE) (Leslie, K O et al. (2007) Semin Respir Crit. Care Med. 28:369-78; Swigris, J J et al.
  • Pulmonary fibrosis can also be a side effect of certain medical treatments, particularly radiation therapy to the chest and certain medicines like bleomycin, methotrexate, amiodarone, busulfan, and nitrofurantoin (Catane, R et al.
  • idiopathic pulmonary fibrosis can occur where no clear causal agent or disease can be identified.
  • genetic factors can play a significant role in these cases of pulmonary fibrosis (Steele, M P et al. (2007) Respiration 74:601-8; Brass, D M et al. (2007) ProcAm Thorac Soc. 4:92-100 and du Bois R M. (2006) Semin Respir Crit. Care Med. 27:581-8).
  • the fibrotic condition of the lung can be chosen from one or more of: pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), or bronchiectasis.
  • pulmonary fibrosis idiopathic pulmonary fibrosis (IPF)
  • UPF idiopathic pulmonary fibrosis
  • UIP interstitial pneumonitis
  • CFA cryptogenic fibrosing alveolitis
  • bronchiectasis bronchiectasis
  • the pulmonary fibrosis can include, but is not limited to, pulmonary fibrosis associated with chronic obstructive pulmonary disease (COPD), scleroderma, pleural fibrosis, chronic asthma, acute lung syndrome, amyloidosis, bronchopulmonary dysplasia, Caplan's disease, Dressler's syndrome, histiocytosis X, idiopathic pulmonary haemosiderosis, lymphangiomyomatosis, mitral valve stenosis, polymyositis, pulmonary edema, pulmonary hypertension (e.g., idiopathic pulmonary hypertension (IPH)), pneumoconiosis, radiotherapy (e.g., radiation induced fibrosis), rheumatoid disease, Shaver's disease, systemic lupus erythematosus, systemic sclerosis, tropical pulmonary eosinophilia, tuberous sclerosis, Weber-Christian disease,
  • the pulmonary fibrosis is associated with an inflammatory disorder of the lung, e.g., asthma, COPD.
  • the fibrotic condition can be a fibrotic condition of the liver (also referred to herein as“hepatic fibrosis”), such as fatty liver disease e.g., steatosis such as nonalcoholic steatohepatitis (NASH), biliary fibrosis, cholestatic liver disease (e.g., primary biliary cirrhosis (PBC), and cholangiopathies (e.g., chronic cholangiopathies)).
  • fatty liver disease e.g., steatosis such as nonalcoholic steatohepatitis (NASH), biliary fibrosis, cholestatic liver disease (e.g., primary biliary cirrhosis (PBC), and cholangiopathies (e.g., chronic cholangiopathies)
  • NASH nonalcoholic steatohepatitis
  • PBC primary biliary cirrhosis
  • cholangiopathies e.
  • the fibrotic of the liver or hepatic fibrosis can be chosen from one or more of: fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis
  • NASH cholestatic liver disease
  • PBC primary biliary cirrhosis
  • biliary fibrosis cirrhosis
  • alcohol induced liver fibrosis biliary duct injury, infection or viral induced liver fibrosis
  • congenital hepatic fibrosis e.g., autoimmune hepatitis
  • cholangiopathies e.g., chronic cholangiopathies
  • hepatic or liver fibrosis includes, but is not limited to, hepatic fibrosis associated with alcoholism, viral infection, e.g., hepatitis (e.g., hepatitis C, B or D), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, pharmaceutical drugs and environmental toxins such as arsenic), alpha-1 antitrypsin deficiency, hemochromatosis, Wilson's disease, galactosemia, or glycogen storage disease.
  • the hepatic fibrosis is associated with an inflammatory disorder of the liver.
  • the fibrotic condition can be a fibrotic condition of the heart or vasculature, such as myocardial fibrosis.
  • Fibrotic conditions of the heart or vasculature can include, but are not limited to, myocardial fibrosis (e.g., myocardial fibrosis associated with radiation myocarditis, a surgical procedure complication (e.g., myocardial post operative fibrosis), vascular restenosis, atherosclerosis, cerebral disease, peripheral vascular disease, infectious diseases (e.g., Chagas disease, bacterial, trichinosis or fungal
  • myocarditis myocarditis
  • granulomatous e.g., metabolic storage disorders (e.g., cardiomyopathy, hemochromatosis); developmental disorders (e.g., endocardial fibroelastosis);
  • the myocardial fibrosis is associated with an inflammatory disorder of cardiac tissue (e.g., myocardial sarcoidosis).
  • the fibrotic condition can be a fibrotic condition of the kidney, such as renal fibrosis (e.g., chronic kidney fibrosis).
  • Renal fibrosis can include, but is not limited to, nephropathies associated with injury/fibrosis (e.g., chronic nephropathies associated with diabetes (e.g., diabetic nephropathy)), lupus, scleroderma of the kidney, glomerular nephritis, focal segmental glomerular sclerosis, IgA nephropathyrenal fibrosis associated with human chronic kidney disease (CKD), chronic kidney fibrosis, nephrogenic systemic fibrosis, chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction (e.g., fetal partial urethral obstruction), chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis (e
  • the kidney fibrosis is mediated by a bone morphogeneic protein (BMP).
  • BMP bone morphogeneic protein
  • the renal fibrosis is a result of an inflammatory disorder of the kidney.
  • the fibrotic condition can be a fibrotic condition of the bone marrow.
  • the fibrotic condition of the bone marrow is myelofibrosis (e.g., primary myelofibrosis (PMF)), myeloid metaplasia, chronic idiopathic myelofibrosis, or primary myelofibrosis.
  • bone marrow fibrosis is associated with a hematologic disorder chosen from one or more of hairy cell leukemia, lymphoma, or multiple myeloma.
  • the bone marrow fibrosis can be associated with one or more myeloproliferative neoplasms (MPN) chosen from: essential thrombocythemia (ET), polycythemia vera (PV), mastocytosis, chronic eosinophilic leukemia, chronic neutrophilic leukemia, or other MPN.
  • MPN myeloproliferative neoplasms
  • the fibrotic condition can be primary myelofibrosis.
  • Primary myelofibrosis (PMF) (also referred to in the literature as idiopathic myeloid metaplasia, and Agnogenic myeloid metaplasia) is a clonal disorder of multipotent hematopoietic progenitor cells (reviewed in Abdel-Wahab, O. et al. (2009) Annu. Rev. Med. 60:233-45; Varicchio, L. et al. (2009) Expert Rev. Hematol. 2(3):315-334; Agrawal, M. et al. (2010) Cancer 1-15).
  • the disease is characterized by anemia, splenomegaly and extramedullary hematopoiesis, and is marked by progressive marrow fibrosis and atypical megakaryocytic hyperplasia.
  • CD34+ stem/progenitor cells abnormally traffic in the peripheral blood and multi organ extramedullary erythropoiesis is a hallmark of the disease, especially in the spleen and liver.
  • the bone marrow structure is altered due to progressive fibrosis, neoangiogenesis, and increased bone deposits.
  • a significant percentage of patients with PMF have gain-of- function mutations in genes that regulate hematopoiesis, including Janus kinase 2 (JAK2) ( ⁇ 50%) (e.g., JAK2 V617F ) or the thrombopoietin receptor (MPL) (5-10%), resulting in abnormal megakaryocyte growth and differentiation.
  • JAK2 V617F Janus kinase 2
  • MPL thrombopoietin receptor
  • Bone marrow fibrosis can be observed in several other hematologic disorders including, but not limited to hairy cell leukemia, lymphoma, and multiple myeloma.
  • the bone marrow fibrosis can be secondary to non- hematologic disorders, including but not limited to, solid tumor metastases to bone marrow, autoimmune disorders (systemic lupus erythematosus, scleroderma, mixed connective tissue disorder, polymyositis), and secondary hyperparathyroidism associated with vitamin D deficiency (see Abdel-Wahab, O. et al. (2009) supra at page 235). In most cases, it is possible to distinguish between these disorders and PMF, although in rare cases the presence of the JAK2V617F or MPLW515L/K mutation can be used to demonstrate the presence of a clonal MPN and to exclude the possibility of reactive fibrosis.
  • non- hematologic disorders including but not limited to, solid tumor metastases to bone marrow, autoimmune disorders (systemic lupus erythematosus, scleroderma, mixed connective tissue disorder, polymyositis), and secondary hyperpara
  • monitoring a clinical improvement in a subject with bone marrow fibrosis can be evaluated by one or more of: monitoring peripheral blood counts (e.g., red blood cells, white blood cells, platelets), wherein an increase in peripheral blood counts is indicative of an improved outcome.
  • monitoring peripheral blood counts e.g., red blood cells, white blood cells, platelets
  • clinical improvement in a subject with bone marrow fibrosis can be evaluated by monitoring one or more of: spleen size, liver size, and size of extramedullary hematopoiesis, wherein a decrease in one or more of these parameters is indicative of an improved outcome.
  • the fibrotic condition can be a fibrotic condition of the skin.
  • the fibrotic condition is chosen from one or more of: skin fibrosis and/or scarring, post-surgical adhesions, scleroderma (e.g., systemic scleroderma), or skin lesions such as keloids.
  • the fibrotic condition can be a fibrotic condition of the gastrointestinal tract.
  • Such fibrotic conditions can be associated with an inflammatory disorder of the gastrointestinal tract, e.g., fibrosis associated with scleroderma; radiation induced gut fibrosis; fibrosis associated with a foregut inflammatory disorder such as Barrett's esophagus and chronic gastritis, and/or fibrosis associated with a hindgut inflammatory disorder, such as inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease.
  • IBD inflammatory bowel disease
  • ulcerative colitis Crohn's disease
  • the fibrotic condition can be diffuse scleroderma.
  • Fibrotic conditions can further include diseases that have as a manifestation fibrotic disease of the penis, including Peyronie's disease (fibrosis of the cavernous sheaths leading to contracture of the investing fascia of the corpora, resulting in a deviated and painful erection).
  • diseases that have as a manifestation fibrotic disease of the penis including Peyronie's disease (fibrosis of the cavernous sheaths leading to contracture of the investing fascia of the corpora, resulting in a deviated and painful erection).
  • the fibrotic condition can comprise Dupuytren’s contracture (palmar fibromatosis).
  • the fibrotic condition can comprise fibrosis associated with rheumatoid arthritis.
  • the fibrotic condition can be selected from pulmonary fibrosis, bronchiectasis, interstitial lung disease; fatty liver disease; cholestatic liver disease, biliary fibrosis, hepatic fibrosis; myocardial fibrosis; and renal fibrosis.
  • the fibrotic condition can be selected from biliary fibrosis, hepatic fibrosis, pulmonary fibrosis, myocardial fibrosis and renal fibrosis
  • the fibrotic condition can be selected from nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • fibrotic conditions that can be treated with the methods and compositions of the invention include cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, sarcoidosis, scleroderma, spinal cord injury/fibrosis.
  • ERp agonists can be readily used to evaluate whether fibrosis is ameliorated in such models.
  • models include but are not limited to, the unilateral ureteral obstruction model of renal fibrosis (see Chevalier et al.,“Ureteral Obstruction as a Model of Renal Interstitial Fibrosis and Obstructive Nephropathy” Kidney International (2009) 75: 1145-1152), the bleomycin induced model of pulmonary fibrosis (see Moore and Hogaboam“Murine Models of Pulmonary Fibrosis” Am. J Physiol. Lung. Cell. Mol. Physiol.
  • liver/biliary fibrosis models see Chuang et al.,“Animal Models of Primary Biliary Cirrhosis” Clin Liver Dis (2008) 12:333- 347; Omenetti, A. et al. (2007) Laboratory Investigation 87:499-514 (biliary duct-ligated model); or a number of myelofibrosis mouse models as described in Varicchio, L. (2009) supra.
  • ERp agonists can be evaluated in essentially three paradigms: 1) test whether ERp agonists can inhibit the fibrotic state; 2) test whether ERp agonists can stop fibrotic progression once initiated; and/or 3) test whether ERP agonists can reverse the fibrotic state once initiated.
  • the fibrotic condition is provided in a tissue (e.g., biliary tissue, liver tissue, lung tissue, heart tissue, kidney tissue, skin tissue, gut tissue, or neural tissue).
  • tissue e.g., biliary tissue, liver tissue, lung tissue, heart tissue, kidney tissue, skin tissue, gut tissue, or neural tissue.
  • the tissue is biliary tissue.
  • the tissue is liver tissue.
  • the tissue is lung tissue.
  • the tissue is heart tissue. In certain embodiments, the tissue is kidney tissue. In certain embodiments, the tissue is skin tissue. In certain embodiments, the tissue is gut tissue. In certain embodiments, the tissue is bone marrow tissue. In certain embodiments, the tissue is epithelial tissue. In certain embodiments, the tissue is neural tissue. Also provided are composition for use, and use of, an ERp agonist, alone or in combination with another agent, for preparation of one or more medicaments for use in reducing fibrosis, or treatment of a fibrotic condition.
  • the above-described methods can comprise providing an ERp agonist in a pharmaceutical composition.
  • compositions can be formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (e.g., aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), capsules, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection such as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; intravaginally or intrarectally, for example, as a pessary, cream or foam; sublingually; ocularly;
  • oral administration for example, drenches (e.g., aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal
  • Pharmaceutically acceptable excipients include any and all fillers, binders, surfactants, disintegrants, sugars, polymers, antioxidants, solubilizing or suspending agents, chelating agents, preservatives, buffering agents and/or lubricating agents, or combinations thereof, as suited to the particular dosage form desired and according to the judgment of the formulator.
  • Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various pharmaceutically acceptable excipients used in preparing compositions and known techniques for the preparation thereof.
  • compositions are prepared by uniformly and intimately bringing into association the agonist with one or more excipients and then, if necessary, shaping the product.
  • the agonist When the agonist is administered to humans or animals it can be given per se or as a pharmaceutical composition containing, for example, about 0.1 to 99%, or about 10 to 50%, or about 10 to 40%, or about 10 to 30%, or about 10 to 20%, or about 10 to 15% of the agonist in combination with a pharmaceutically acceptable excipient.
  • Actual dosage levels of the agonist in the pharmaceutical compositions can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.
  • the selected dosage level will depend upon a variety of factors including, for example, the activity of the particular agonist employed, the route of administration, the time of administration, the rate of excretion or metabolism, the rate and extent of absorption, the duration of the treatment, other drugs, compounds or materials used in combination with the agonist, the age, sex, weight, condition, general health and prior medical history of the subject, and other similar factors well known in the medical arts.
  • a suitable daily dose of an agonist will be that amount which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • oral, intravenous and subcutaneous doses of the agonist for a subject when used for the indicated effects, will range from about 0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg per day, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about 100 mg per day, or about 0.0001 mg to about 500 mg per day, or about 0.001 mg to about 500 mg per day, or about 0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg per day.
  • the subject receiving the treatment can be any animal in need, including primates (e.g. humans), equines, cattle, swine, sheep, poultry, dogs, cats, mice and rats.
  • the agonist can be administered daily, every other day, three times a week, twice a week, weekly, or bi-weekly.
  • the dosing schedule can include a“drug holiday,” i.e., the drug can be administered for two weeks on, one week off, or three weeks on, one week off, or four weeks on, one week off, etc., or continuously, without a drug holiday.
  • the agonist can be administered orally, intravenously, intraperitoneally, topically, transdermally,
  • the ERP agonists can be administered in combination with one or more therapeutic agents.
  • therapeutic agents include, but are not limited to, anti-fibrotics, corticosteroids, anti-inflammatories, immunosuppressants, chemotherapeutic agents, anti metabolites, and immunomodulators.
  • the therapeutic agent and the agonist must be administered at the same time and/or formulated for delivery together, although these methods of delivery are possible.
  • the agonist can be administered concurrently with, prior to, or subsequent to, one or more other additional agents.
  • each therapeutic agent will be administered at a dose and/or on a time schedule determined for that particular agent.
  • the therapeutic agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the agonist with the agent and/or the desired therapeutic effect to be achieved.
  • the agonist is a first line treatment for the fibrotic condition, i.e., it is used in a subject who has not been previously administered another drug intended to treat the condition.
  • the agonist is a second line treatment for
  • the fibrotic condition i.e., it is used in a subject who has been previously administered another drug intended to treat the condition.
  • the agonist is a third or fourth line treatment for
  • the fibrotic condition i.e., it is used in a subject who has been previously administered two or three other drugs intended to treat the condition.
  • the agonist is administered to a subject following a surgical procedure, such as a surgical excision/removal of tissue.
  • a agonist is administered to a subject before, during, and/or after radiation treatment.
  • the two agents can be administered concurrently (i.e., essentially at the same time, or within the same treatment) or sequentially (i.e., one immediately following the other, or alternatively, with a gap in between administration of the two).
  • the agonist is administered sequentially (i.e., after the first therapeutic).
  • the agonist can be administered in combination with an agent chosen from a Jak2 inhibitor (including, but not limited to, INCB018424, XL019, TG101348, or TG101209), an immunomodulator, e.g., an IMID (including, but not limited to thalidomide, lenalidomide, or panolinomide), hydroxyurea, an androgen, erythropoietic stimulating agents, prednisone, danazol, HD AC inhibitors, or other agents or therapeutic modalities (e.g., stem cell transplants, or radiation).
  • a Jak2 inhibitor including, but not limited to, INCB018424, XL019, TG101348, or TG101209
  • an immunomodulator e.g., an IMID (including, but not limited to thalidomide, lenalidomide, or panolinomide), hydroxyurea, an androgen, erythropoietic stimulating agents, prednisone,
  • Suitable therapeutics for use in combination with the agonist for treatment of heart fibrosis includes, but is not limited to, eplerenone, furosemide, pycnogenol, spironolactone, TcNC 100692, torasemide (e.g., prolonged release form of torasemide), and combinations thereof.
  • kidney fibrosis includes, but is not limited to, cyclosporine, cyclosporine A, daclizumab, everolimus, gadofoveset trisodium (ABLAVAR®), imatinib mesylate
  • Suitable therapeutics for use in combination with the agonist for treatment of skin fibrosis includes, but is not limited to, Bosentan (Tracleer), pl44, pentoxifylline; pirfenidone; pravastatin, STI571, Vitamin E, and combinations thereof.
  • Suitable therapeutics for use in combination with the agonist for treatment of gastrointestinal fibrosis includes, but is not limited to, ALTEi-135, bucelipase alfa (INN), DCI1020, EUR-1008 (ZENPEPTM), ibuprofen, Lym-X-Sorb powder, pancrease MT, pancrelipase (e.g., pancrelipase delayed release), pentade canoic acid (PA), repaglinide, TheraCLECTM, triheptadecanoin (THA), ULTRASE MT20, ursodiol, and combinations thereof.
  • Suitable therapeutics for use in combination with the agonist for treatment of lung fibrosis includes, but is not limited to, 18-FDG, AB0024, ACT-064992 (macitentan), aerosol interferon-gamma, aerosolized human plasma-derived alpha- 1 antitrypsin, alpha 1 -proteinase inhibitor, ambrisentan, amikacin, amiloride, amitriptyline, anti-pseudomonas IgY gargle, ARIKACETM, AUREXIS® (tefibazumab), AZAPRED, azathioprine, azithromycin, azithromycin, AZLI, aztreonam lysine, BIBF1120, Bio-25 probiotic, bosentan, Bramitob®, calfactant aerosol, captopril, CC-930, ceftazidime, ceftazidime, cholecalciferol (Vitamin D3), cipr
  • aeruginosa immune globulin IV mycophenolate mofetil, n-acetylcysteine, N-acetylcysteine (NAC), NaCl 6%, nitric oxide for inhalation, obramycin, octreotide, oligoG CF-5/20, Omalizumab, pioglitazone, piperacillin-tazobactam, pirfenidone, pomalidomide (CC-4047), prednisone, prevastatin, PRM-151, QAX576, rhDNAse, SB656933, SB-656933-AAA, sildenafil, tamoxifen, technetium [Tc-99 m] sulfur colloid and Indium [In-111] DTPA,
  • tetrathiomolybdate thalidomide, ticarcillin-clavulanate, tiotropium bromide, tiotropium RESPIMAT® inhaler, tobramycin (GERNEBCIN®), treprostinil, uridine, valganciclovir (VALCYTE®), vardenafil, vitamin D3, xylitol, zileuton, and combinations thereof.
  • Suitable therapeutics for use in combination with the agonist for treatment of liver fibrosis includes, but is not limited to, adefovir dipivoxil, candesartan, colchicine, combined ATG, mycophenolate mofetil, and tacrolimus, combined cyclosporine microemulsion and tacrolimus, elastometry, everolimus, FG-3019, Fuzheng Huayu, GI262570, glycyrrhizin (monoammonium glycyrrhizinate, glycine, L-cysteine
  • An example of other suitable therapeutics for use in combination with the agonist for treatment of cystic fibrosis includes, but is not limited to, 552-02, 5- methyltetrahydrofolate and vitamin B 12, Ad5-CB-CFTR, Adeno-associated virus-CFTR vector, albuterol, alendronate, alpha tocopherol plus ascorbic acid, amiloride HC1, aquADEKTM, ataluren (PTC 124), AZD1236, AZD9668, azithromycin, bevacizumab, biaxin (clarithromycin), BIIL 283 BS (amelubent), buprofen, calcium carbonate, ceftazidime, cholecalciferol, choline supplementation, CPX, cystic fibrosis transmembrane conductance regulator, DHA-rich supplement, digitoxin, cocosahexaenoic acid (DHA), doxycycline, ECGC, ecombinant human IGF-1, e
  • QAU145 salmeterol, SB656933, SB656933, simvastatin, sitagliptin, sodium 4- phenylbutyrate, standardized turmeric root extract, tgAAVCF, TNF blocker, TOBI, tobramycin, tocotrienol, unconjugated Isoflavones 100, vitamin: choline bitartrate (2- hydroxy ethyl) trimethylammonium salt 1 : 1, VX-770, VX-809, Zinc acetate, and combinations thereof.
  • Compound l is a selective estrogen receptor beta (ERP) agonist.
  • EBP estrogen receptor beta
  • the in vivo efficacy of compound 1 was evaluated in a STAM model of non-alcoholic steatohepatitis (NASH, a fibrotic condition).
  • Compound 1 was prepared using methods described previously. To prepare dosing solutions, compound 1 was weighed and suspended in vehicle (5% DMSO, 5% Tween ® 20, water). Compound 1 was administered orally in a volume of lOmL/kg. Compound 1 was administered at two dose levels of 10 and 100 mg/kg once daily.
  • vehicle 5% DMSO, 5% Tween ® 20, water.
  • Compound 1 was administered orally in a volume of lOmL/kg. Compound 1 was administered at two dose levels of 10 and 100 mg/kg once daily.
  • NASH 14 day-pregnant C57BU6 mice were obtained for use in this study. All animals used in this study were housed and cared for in accordance with industry standards.
  • mice Individual body weight was measured daily during the treatment period. Survival, clinical signs, and behavior of the mice was also monitored daily.
  • Plasma Biochemistry To evaluate plasma biochemistry, non- fasting blood was collected in polypropylene tubes with anticoagulant (Novo-Heparin, Mochida Pharmaceutical Co. Ltd., Japan) and centrifuged at 1 ,000 xg for 1 5 minutes at 4°C. The supernatant was collected and stored at -8Q°C until use. Plasma ALT levels were measured by FUJI DRJ-CHEM 7000 (Fujifilm, Japan)
  • Liver total lipid-extracts were obtained by Folch's method (Folch J. et al, J. Biol. Chem. 1957;226: 497). Liver samples were homogenized in chloroform-methanol (2: 1, v/v) and incubated overnight at room
  • HE staining sections were cut from paraffin blocks of liver tissue prefixed in Bouin's solution and stained with Lillie- Mayer's Hematoxylin (Muto Pure Chemicals Co., Ltd., Japan) and eosin solution (Wako Pure Chemical Industries). NAFLD Activity score (NAS) was calculated according to the criteria of Kleiner (Kleiner DE. et al, Hepatology, 2005;41 : 1313). To visualize collagen deposition, Bouin's fixed liver sections were stained using picro-Sirius red solution (Waldeck, Germany).
  • the remaining pieces of left lateral lobe were embedded in O.C.T. compound and quick frozen in liquid nitrogen.
  • O.C.T. blocks were stored at -80°C.
  • the right lobe was snap frozen in liquid nitrogen and stored at -80°C for liver biochemistry.
  • Group 1 Normal. Eight normal mice were kept without any treatment until sacrifice.
  • Group 2 Vehicle. Eight NASH mice were orally administered vehicle (5%
  • DMSO 5% Tween ® 20, water
  • Group 3 Compound High. Eight NASH mice were orally administered vehicle supplemented with compound 1 at a dose of 100 mL/kg once daily from 5 to 12 weeks of age.
  • Group 4 Compound Low. Eight NASH mice were orally administered vehicle supplemented with compound 1 at a dose of 10 mL/kg once daily from 5 to 12 weeks of age.
  • Figure 1 illustrates the average body weight change observed in the four study groups over the course of the treatment period. Mean body weight in all groups gradually increased during the treatment period. Mean body weights of the Vehicle group were significantly lower than that of the Normal group from Day 0 to Day 49. There were no significant differences in mean body weights at any day during the treatment period between the Vehicle group and the Compound treatment groups.
  • mice found dead before reaching Day 49 were as follows; three out of 8 mice were found dead in the Vehicle group. Two out of 8 mice were found dead in the Compound high and Compound low groups.
  • FIG. 2A is a plot showing the body weight of animals on the day of sacrifice.
  • the Vehicle group showed a significant decrease in mean body weight on the day of sacrifice compared with the Normal group. There were no significant differences in mean body weight on the day of sacrifice between the Vehicle group and the Compound treatment groups.
  • Figure 2B is a plot showing the liver weight of animals on the day of sacrifice.
  • the Vehicle group showed a significant increase in mean liver weight compared with the Normal group. There were no significant differences in mean liver weight between the Vehicle group and the Compound treatment groups
  • Figure 2C is a plot showing the liver-to-body weight ratio of animals on the day of sacrifice.
  • the Vehicle group showed a significant increase in mean liver-to-body weight ratio compared with the Normal group.
  • Mean liver-to-body weight ratio in the Compound high group tended to increase compared with the Vehicle group.
  • There was no significant difference in mean liver-to-body weight ratio between the Vehicle group and the Compound low group The results of these studies are summarized in the table below.
  • Figure 3 A is a plot showing the plasma alanine aminotransferase (ALT) levels on the day of sacrifice.
  • the Vehicle group showed a significant increase in plasma ALT level compared with the Normal group.
  • the Compound high and low groups showed significant decreases in plasma ALT levels compared with the Vehicle group
  • Figure 3B is a plot showing liver triglyceride levels (in mg/g liver) on the day of sacrifice.
  • the Vehicle group showed a significant increase in liver triglyceride content compared with the Normal group.
  • the Compound high and low groups showed significant decreases in liver triglyceride compared with the Vehicle group.
  • Liver sections from the Vehicle group exhibited micro- and macrovesicular fat deposition, hepatocellular ballooning and inflammatory cell infiltration compared with the Normal group.
  • the Vehicle group showed a significant increase in NAS compared with the Normal group.
  • NAS in the Compound high and low groups tended to decrease compared with the Vehicle group.
  • Figure 4 is a plot showing the non-alcoholic fatty liver disease (NAFLD) activity score on the day of sacrifice.
  • Figure 5A is a plot showing the steatosis score on the day of sacrifice.
  • Figure 5B is a plot showing the inflammation score on the day of sacrifice.
  • Figure 5C is a plot showing the ballooning score on the day of sacrifice.
  • liver sections were stained with Sirius Red an imaged, and the positive area was determined as described above.
  • Liver sections from the Vehicle group showed increased collagen deposition in the pericentral region of liver lobule compared with the Normal group.
  • the Vehicle group showed a significant increase in the fibrosis area (Sirius red-positive area) compared with the Normal group.
  • Compound high group showed a significant decrease in the fibrosis area compared with the Vehicle group.
  • Figure 6 is a plot showing the fibrosis area (sirius red-positive area, %) on the day of sacrifice. The results of these studies are summarized in the table below.
  • Treatment with compound 1 showed significant reduction in plasma ALT levels and liver triglycelide content compared with Vehicle group.
  • Treatment with compound 1 showed a decreasing trend in NAFLD Activity Score (NAS) compared with Vehicle group.
  • Treatment with compound 1 of high dose showed significant reduction in the fibrosis area compared with Vehicle group, in a dose dependent manner.
  • NAS NAFLD Activity Score
  • the compound 1 showed hepatoprotective potential, anti-steatosis and anti-fibrosis effects in this NASH model
  • compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims. Any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other

Abstract

Disclosed are method of treating fibrotic conditions using estrogen receptor β (ERβ) agonists.

Description

Estrogen Receptor Beta (ERp) Agonists for the Treatment of
Fibrotic Conditions
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims benefit of U.S. Provisional Application No. 62/798,715, filed January 30, 2019, which is hereby incorporated herein by reference in its entirety.
BACKGROUND
The process of tissue repair as a part of wound healing involves two phases. The first phase is the regenerative phase, in which injured cells are replaced by cells of the same type. The second phase is the formation of fibrous tissues, also called fibroplasia or fibrosis, in which connective tissue replaces normal parenchymal tissues. The tissue repair process can become pathogenic if the fibrosis phase continues unchecked, leading to extensive tissue remodeling and the formation of permanent scar tissue.
It has been estimated that up to 45% of deaths in the United States can be attributed to fibroproliferative diseases, which can affect many tissues and organ systems. Major organ fibrotic diseases include interstitial lung disease (ILD), characterized by pulmonary inflammation and fibrosis. ILD is known to have a number of causes such as sarcoidosis, silicosis, collagen vascular diseases, and systemic scleroderma. However, idiopathic pulmonary fibrosis, a common type of ILD, has no known cause. Other
organ fibrotic disorders include liver cirrhosis, liver fibrosis resulting from chronic hepatitis B or C infection, kidney disease, heart disease, and eye diseases including macular degeneration and retinal and vitreal retinopathy. Fibroproliferative disorders also include systemic and local scleroderma, keloids and hypertrophic scars, atherosclerosis, and restenosis. Additional fibroproliferative diseases include excessive scarring resulting from surgery, chemotherapeutic drug-induced fibrosis, radiation-induced fibrosis, and injuries and burns.
Currently, treatments are available for fibrotic disorders including general immunosuppressive drugs such as corticosteroids, and other anti-inflammatory treatments. However, the mechanisms involved in regulation of fibrosis appear to be distinctive from those of inflammation, and anti-inflammatory therapies are not always effective in reducing or preventing fibrosis. Therefore, a need remains for developing treatments to reduce and prevent fibrosis and control fibrotic disorders. SUMMARY
Disclosed are methods of treating fibrotic conditions using estrogen receptor beta (ERP) agonists. In certain embodiments, the fibrotic condition can comprise a fibrotic condition of the liver, such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
DESCRIPTION OF DRAWINGS
Figure 1 illustrates the average body weight change observed in the four study groups over the course of the treatment period.
Figure 2A is a plot showing the body weight of animals on the day of sacrifice.
Figure 2B is a plot showing the liver weight of animals on the day of sacrifice.
Figure 2C is a plot showing the liver-to-body weight ratio of animals on the day of sacrifice.
Figure 3 A is a plot showing plasma alanine aminotransferase (ALT) levels (in U/L) on the day of sacrifice.
Figure 3B is a plot showing liver triglyceride levels (in mg/g liver) on the day of sacrifice.
Figure 4 is a plot showing the non-alcoholic fatty liver disease (NAFLD) activity score on the day of sacrifice.
Figure 5 A is a plot showing the steatosis score on the day of sacrifice.
Figure 5B is a plot showing the inflammation score on the day of sacrifice.
Figure 5C is a plot showing the ballooning score on the day of sacrifice.
Figure 6 is a plot showing the fibrosis area (sirius red-positive area, %) on the day of sacrifice.
DETAILED DESCRIPTION
In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings.
Throughout the description and claims of this specification the word“comprise” and other forms of the word, such as“comprising” and“comprises,” means including but not limited to, and is not intended to exclude, for example, other additives, components, integers, or steps.
As used in the description and the appended claims, the singular forms“a,”“an,” and“the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to“a composition” includes mixtures of two or more such compositions, reference to“an agent” includes mixtures of two or more such agents, reference to“the component” includes mixtures of two or more such components, and the like.
“Optional” or“optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
Ranges can be expressed herein as from“about” one particular value, and/or to “about” another particular value. By“about” is meant within 5% of the value, e.g., within 4, 3, 2, or 1% of the value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.
It is understood that throughout this specification the identifiers“first” and“second” are used solely to aid in distinguishing the various components and steps of the disclosed subject matter. The identifiers“first” and“second” are not intended to imply any particular order, amount, preference, or importance to the components or steps modified by these terms.
As used herein, by a“subject” is meant an individual. Thus, the“subject” can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g, cattle, horses, pigs, sheep, goats, etc.), laboratory animals (e.g, mouse, rabbit, rat, guinea pig, etc.), and birds. “Subject” can also include a mammal, such as a primate or a human. Thus, the subject can be a human or veterinary patient. The term“patient” refers to a subject under the treatment of a clinician, e.g., physician.
As used herein,“fibrotic condition” refers to a disease or condition involving the formation and/or deposition of fibrous tissue, e.g., excessive connective tissue builds up in a tissue and/or spreads over or replaces normal organ tissue (reviewed in, e.g., Wynn, Nature Reviews 4:583-594 (2004) and Abdel-Wahab, O. et al. (2009) Annu. Rev. Med. 60:233-45, incorporated herein by reference). In certain embodiments, the fibrotic condition involves excessive collagen mRNA production and deposition. In certain embodiments,
the fibrotic condition is caused, at least in part, by injury, e.g., chronic injury (e.g., an insult, a wound, a toxin, a disease). In certain embodiments, the fibrotic condition is associated with an inflammatory, an autoimmune or a connective tissue disorder. For example, chronic inflammation in a tissue can lead to fibrosis in that tissue. Exemplary fibrotic tissues include, but are not limited to, biliary tissue, liver tissue, lung tissue, heart tissue, vascular tissue, kidney tissue, skin tissue, gut tissue, peritoneal tissue, bone marrow, and the like. In certain embodiments, the tissue is epithelial tissue.
“Treating,”“treat,” and“treatment” as used herein, refers to partially or completely inhibiting or reducing the fibrotic condition which the subject is suffering. In one embodiment, this term refers to an action that occurs while a patient is suffering from, or is diagnosed with, the fibrotic condition, which reduces the severity of the condition, or retards or slows the progression of the condition. Treatment need not result in a complete cure of the condition; partial inhibition or reduction of the fibrotic condition is encompassed by this term.
“Therapeutically effective amount,” as used herein, refers to a minimal amount or concentration of an ERP agonist that, when administered alone or in combination, is sufficient to provide a therapeutic benefit in the treatment of the condition, or to delay or minimize one or more symptoms associated with the condition. The term“therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, or enhances the therapeutic efficacy of another therapeutic agent. The therapeutic amount need not result in a complete cure of the condition; partial inhibition or reduction of the fibrotic condition is encompassed by this term.
As used herein, unless otherwise specified, the terms“prevent,”“preventing” and “prevention” refers to an action that occurs before the subject begins to suffer from the condition, or relapse of such condition. The prevention need not result in a complete prevention of the condition; partial prevention or reduction of the fibrotic condition is encompassed by this term.
As used herein, unless otherwise specified, a“prophylactically effective amount” of a ERP that, when administered alone or in combination, prevent the condition, or one or more symptoms associated with the condition, or prevent its recurrence. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. The prophylactic amount need not result in a complete prevention of the condition; partial prevention or reduction of the fibrotic condition is encompassed by this term. The term“pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.
Chemical Definitions
Terms used herein will have their customary meaning in the art unless specified otherwise. The organic moieties mentioned when defining variable positions within the general formulae described herein (e.g., the term“halogen”) are collective terms for the individual substituents encompassed by the organic moiety. The prefix Cn-Cm preceding a group or moiety indicates, in each case, the possible number of carbon atoms in the group or moiety that follows.
As used herein, the term“substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, heteroatoms present in a compound or moiety, such as nitrogen, can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valency of the heteroatom. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or“substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound (e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
“Z1,”“Z2,”“Z3,” and“Z4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
As used herein, the term“alkyl” refers to saturated, straight-chained or branched saturated hydrocarbon moieties. Unless otherwise specified, C1-C24 (e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, or C1-C4) alkyl groups are intended. Examples of alkyl groups include methyl, ethyl, propyl, 1 -methyl-ethyl, butyl, 1 -methyl- propyl, 2-methyl-propyl, 1,1 -dimethyl-ethyl, pentyl, 1 -methyl-butyl, 2-methyl-butyl, 3- methyl-butyl, 2,2-dimethyl-propyl, 1 -ethyl -propyl, hexyl, 1,1 -dimethyl-propyl, 1,2- dimethyl-propyl, 1 -methyl-pentyl, 2-methyl-pentyl, 3 -methyl-pentyl, 4-methyl-pentyl, 1,1- dimethyl -butyl , 1,2-dimethyl-butyl, 1,3-dimethyl-butyl, 2,2-dimethyl-butyl, 2,3-dimethyl- butyl, 3, 3 -dimethyl-butyl, 1 -ethyl-butyl, 2-ethyl-butyl, 1,1,2-trimethyl-propyl, 1,2,2- trimethyl-propyl, 1 -ethyl- 1 -methyl-propyl, and l-ethyl-2-methyl-propyl. Alkyl substituents may be unsubstituted or substituted with one or more chemical moieties. The alkyl group can be substituted with one or more groups including, but not limited to, hydroxy, halogen, acyl, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied.
Throughout the specification“alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term“halogenated alkyl” specifically refers to an alkyl group that is substituted with one or more halides (halogens; e.g., fluorine, chlorine, bromine, or iodine). The term“alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term“alkylamino” specifically refers to an alkyl group that is substituted with one or more amino groups, as described below, and the like. When“alkyl” is used in one instance and a specific term such as“alkylalcohol” is used in another, it is not meant to imply that the term“alkyl” does not also refer to specific terms such as“alkylalcohol” and the like.
This practice is also used for other groups described herein. That is, while a term such as“cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl” Similarly, a substituted alkoxy can be specifically referred to as, e.g, a“halogenated alkoxy,” a particular substituted alkenyl can be, e.g, an“alkenylalcohol,” and the like. Again, the practice of using a general term, such as“cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term. As used herein, the term“alkenyl” refers to unsaturated, straight-chained, or branched hydrocarbon moieties containing a double bond. Unless otherwise specified, C2- C24 (e.g., C2-C22, C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, C2-C4) alkenyl groups are intended. Alkenyl groups may contain more than one unsaturated bond. Examples include ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1 -methyl- 1-propenyl, 2-methyl- 1-propenyl, l-methyl-2-propenyl, 2 -m ethyl-2 - propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1 -methyl- 1-butenyl, 2-methyl- 1- butenyl, 3 -methyl- 1-butenyl, 1-m ethyl-2 -butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl,
1 -methyl-3 -butenyl, 2-methyl-3 -butenyl, 3 -methyl-3 -butenyl, l,l-dimethyl-2-propenyl, 1,2- dimethyl- 1-propenyl, l,2-dimethyl-2-propenyl, 1 -ethyl- 1-propenyl, l-ethyl-2-propenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1 -methyl- 1-pentenyl, 2-methyl-l- pentenyl, 3 -methyl- 1-pentenyl, 4-methyl- 1-pentenyl, l-methyl-2-pentenyl, 2-methyl-2- pentenyl, 3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1 -methyl-3 -pentenyl, 2-methyl-3- pentenyl, 3 -methyl-3 -pentenyl, 4-methyl-3 -pentenyl, l-methyl-4-pentenyl, 2-methyl-4- pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, l,l-dimethyl-2-butenyl, 1, 1-dimethyl- 3 -butenyl, 1,2-dimethyl- 1-butenyl, l,2-dimethyl-2 -butenyl, l,2-dimethyl-3 -butenyl, 1,3- dimethyl- 1-butenyl, l,3-dimethyl-2-butenyl, l,3-dimethyl-3-butenyl, 2,2-dimethyl-3- butenyl, 2,3 -dimethyl- 1-butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3- dimethyl- 1-butenyl, 3,3-dimethyl-2-butenyl, 1 -ethyl- 1-butenyl, 1 -ethyl-2 -butenyl, 1-ethyl- 3-butenyl, 2-ethyl- 1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3 -butenyl, 1, 1, 2-trimethyl -2- propenyl, 1 -ethyl- l-methyl-2-propenyl, l-ethyl-2-methyl- 1-propenyl, and l-ethyl-2-methyl-
2-propenyl. The term“vinyl” refers to a group having the structure -CEUCEh; 1-propenyl refers to a group with the structure-CEUCEl-CEE; and 2- propenyl refers to a group with the structure -CH2-CEUCH2. Asymmetric structures such as (Z1Z2)C=C(Z3Z4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. Alkenyl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied.
As used herein, the term“alkynyl” represents straight-chained or branched hydrocarbon moieties containing a triple bond. Unless otherwise specified, C2-C24 (e.g., C2- C22, C2-C20, C2-C18, C2-C16, C2-C14, C2-C12, C2-C10, C2-C8, C2-C6, C2-C4) alkynyl groups are intended. Alkynyl groups may contain more than one unsaturated bond. Examples include C2-C6-alkynyl, such as ethynyl, 1-propynyl, 2-propynyl (or propargyl), 1-butynyl, 2- butynyl, 3-butynyl, l-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 3- m ethyl- 1-butynyl, l-methyl-2-butynyl, 1 -methyl-3 -butynyl, 2-methyl-3-butynyl, 1,1- dimethyl-2-propynyl, l-ethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5- hexynyl, 3 -methyl- 1-pentynyl, 4-methyl- 1-pentynyl, l-methyl-2-pentynyl, 4-methyl-2- pentynyl, 1 -methyl-3 -pentynyl, 2-methyl-3-pentynyl, l-methyl-4-pentynyl, 2-methyl-4- pentynyl, 3-methyl-4-pentynyl, l,l-dimethyl-2-butynyl, 1,1 -dimethyl-3 -butynyl, 1,2- dimethyl -3-butynyl, 2, 2-dimethyl-3 -butynyl, 3,3-dimethyl-l-butynyl, 1 -ethyl-2 -butynyl, 1- ethyl -3 -butynyl, 2-ethyl-3 -butynyl, and 1 -ethyl- l-methyl-2-propynyl. Alkynyl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below.
As used herein, the term“aryl,” as well as derivative terms such as aryloxy, refers to groups that include a monovalent aromatic carbocyclic group of from 3 to 20 carbon atoms. Aryl groups can include a single ring or multiple condensed rings. In some embodiments, aryl groups include C6-C10 aryl groups. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. In some embodiments, the aryl group can be a phenyl, indanyl or naphthyl group. The term “heteroaryl” is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. The term“non heteroaryl,” which is included in the term“aryl,” defines a group that contains an aromatic group that does not contain a heteroatom. The aryl or heteroaryl substituents may be unsubstituted or substituted with one or more chemical moieties. Examples of suitable substituents include, for example, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, cycloalkyl, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in the definition of aryl. Biaryl refers to two aryl groups that are bound together via a fused ring structure, as in
naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
The term“cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. The term“heterocycloalkyl” is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein.
The term“cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one double bound, i.e.,
C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. The term“heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term“cycloalkenyl,” where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, acyl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol as described herein.
The term“cyclic group” is used herein to refer to either aryl groups, non-aryl groups (i.e., cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl groups), or both. Cyclic groups have one or more ring systems that can be substituted or unsubstituted. A cyclic group can contain one or more aryl groups, one or more non-aryl groups, or one or more aryl groups and one or more non-aryl groups.
The term“acyl” as used herein is represented by the formula -C(0)Z1 where Z1 can be a hydrogen, hydroxyl, alkoxy, alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above. As used herein, the term“acyl” can be used interchangeably with“carbonyl.” Throughout this specification“C(O)” or“CO” is a short hand notation for C=0.
As used herein, the term“alkoxy” refers to a group of the formula Z'-O-, where Z1 is unsubstituted or substituted alkyl as defined above. Unless otherwise specified, alkoxy groups wherein Z1 is a C1-C24 (e.g., C1-C22, C1-C20, C1-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4) alkyl group are intended. Examples include methoxy, ethoxy, propoxy, 1 -methyl-ethoxy, butoxy, 1-methyl-propoxy, 2-methyl-propoxy, 1,1 -dimethyl- ethoxy, pentoxy, 1-methyl-butyloxy, 2-methyl-butoxy, 3-methyl-butoxy, 2, 2-di -methyl - propoxy, 1-ethyl-propoxy, hexoxy, 1, 1 -dimethyl -propoxy, 1,2-dimethyl -propoxy, 1 -methyl - pentoxy, 2-methyl-pentoxy, 3-methyl-pentoxy, 4-methyl-penoxy, 1, 1 -dimethyl -butoxy, 1,2- dimethyl -butoxy, 1,3 -dimethyl -butoxy, 2,2-dimethyl-butoxy, 2,3-dimethyl-butoxy, 3,3- dimethyl -butoxy, 1 -ethyl -butoxy, 2-ethylbutoxy, 1, 1, 2-trimethyl -propoxy, 1,2,2-trimethyl- propoxy, 1 -ethyl- 1-methyl-propoxy, and l-ethyl-2-methyl-propoxy.
The term“aldehyde” as used herein is represented by the formula— C(0)H.
The terms“amine” or“amino” as used herein are represented by the formula— NZXZ2, where Z1 and Z2 can each be substitution group as described herein, such as hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.“Amido” is — C(0)NZ1Z2.
The term“carboxylic acid” as used herein is represented by the formula— C(0)OH. A“carboxylate” or“carboxyl” group as used herein is represented by the formula—
C(0)0
The term“ester” as used herein is represented by the formula— OC(0)Z1 or — C(0)OZ1, where Z1 can be an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
The term“ether” as used herein is represented by the formula ZlOZ2, where Z1 and Z2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
The term“ketone” as used herein is represented by the formula Z1C(0)Z2, where Z1 and Z2 can be, independently, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
The term“halide” or“halogen” or“halo” as used herein refers to fluorine, chlorine, bromine, and iodine. The term“hydroxyl” as used herein is represented by the formula— OH.
The term“nitro” as used herein is represented by the formula— NO2.
The term“silyl” as used herein is represented by the formula— SiZ1Z2Z3, where Z1, Z2, and Z3 can be, independently, hydrogen, alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula— S(0)2Z', where Z1 can be hydrogen, an alkyl, halogenated alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heterocycloalkenyl group described above.
The term“sulfonylamino” or“sulfonamide” as used herein is represented by the formula— S(0)2NH— .
The term“thiol” as used herein is represented by the formula— SH.
The term“thio” as used herein is represented by the formula— S— .
As used herein, Me refers to a methyl group; OMe refers to a methoxy group; and i- Pr refers to an isopropyl group.
“R1,”“R2,”“R3,”“Rn,” etc., where n is some integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1 is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an amine group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase“an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.
Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible stereoisomer or mixture of stereoisomer (e.g., each enantiomer, each diastereomer, each meso compound, a racemic mixture, or scalemic mixture).
Reference will now be made in detail to specific aspects of the disclosed materials, compounds, compositions, articles, and methods, examples of which are illustrated below. ERp Agonists
Described herein are methods of treating and preventing fibrotic conditions using estrogen receptor beta (ERP) agonists. In some examples, the agonist can have an EC50 of 800 nM or less at estrogen receptor beta (ERP) (e.g., 700 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 40 nM or less, 30 nM or less, 20 nM or less, 10 nM or less, 9 nM or less, 8 nM or less, 7 nM or less, 6 nM or less, 5 nM or less, 4.5 nM or less, 4 nM or less, 3.5 nM or less, 3 nM or less, 2.5 nM or less, 2 nM or less, 1.5 nM or less, 1 nM or less, 0.9 nM or less, 0.8 nM or less, 0.7 nM or less, 0.6 nM or less, 0.5 nM or less, 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, or 0.1 nM or less).
In some examples, the agonist can have an EC50 of 1 pM or more at ERp (e.g., 0.1 nM or more, 0.2 nM or more, 0.3 nM or more, 0.4 nM or more, 0.5 nM or more, 0.6 nM or more, 0.7 nM or more, 0.8 nM or more, 0.9 nM or more, 1 nM or more, 1.5 nM or more, 2 nM or more, 2.5 nM or more, 3 nM or more, 3.5 nM or more, 4 nM or more, 4.5 nM or more, 5 nM or more, 6 nM or more, 7 nM or more, 8 nM or more, 9 nM or more, 10 nM or more, 20 nM or more, 30 nM or more, 40 nM or more, 50 nM or more, 60 nM or more, 70 nM or more, 80 nM or more, 90 nM or more, 100 nM or more, 200 nM or more, 300 nM or more, 400 nM or more, 500 nM or more, 600 nM or more, or 700 nM or more).
The EC50 of the agonist at ERP can range from any of the minimum values described above to any of the maximum values described above. For example, the compounds disclosed herein can have an EC50 of from 1 pM to 800 nM at ERP (e.g., from 1 pM to 400 nM, from 400 nM to 800 nM, from 1 pM to 300 nM, from 1 pM to 200 nM, from 1 pM to 100 nM, from 1 pM to 50 nM, from 1 pM to 20 nM, from 1 pM to 10 nM, from 1 pM to 6 nM, from 1 pM to 5 nM, from 1 pM to 2 nM, from 1 pM to 1 nM, from 1 pM to 0.7 nM, from 1 pM to 0.5 nM, from 1 pM to 0.2 pM, or from 1 pM to 0.1 nM).
In some examples, the agonist can be a selective ERp agonist. In some examples, a selective ERp agonist is a compound that has a lower EC50 at ERp than at estrogen receptor a (ERa). The selectivity of the agonists can, in some examples, be expressed as an ERP-to- ERa agonist ratio, which is the EC50 of the compound at ERa divided by the EC50 of the compound at ERp. In some examples, the agonists can have an ERP-to-ERa agonist ratio of 8 or more (e.g., 10 or more, 20 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 150 or more, 200 or more, 250 or more, 300 or more, 350 or more, 400 or more, 450 or more, 500 or more, 600 or more, 700 or more, 800 or more, 900 or more, 1000 or more, 1100 or more, 1200 or more, 1300 or more, 1400 or more, 1500 or more, 2000 or more, 2500 or more).
In some examples, the agonists can have an ERb-to-ERa agonist ratio of 3000 or less (e.g., 2500 or less, 2000 or less, 1500 or less, 1400 or less, 1300 or less, 1200 or less, 1100 or less, 1000 or less, 900 or less, 800 or less, 700 or less, 600 or less, 500 or less, 450 or less, 400 or less, 350 or less, 300 or less, 250 or less, 200 or less, 150 or less, 100 or less, 90 or less, 80 or less, 70 or less, 60 or less, 50 or less, 40 or less, 30 or less, 20 or less, or 10 or less).
The ERb-to-ERa agonist ratio of the compounds at ERb can range from any of the minimum values described above to any of the maximum values described above. For example, the compounds can have an ERb-to-ERa agonist ratio of from 8 to 3000 (e.g., from 8 to 1500, from 1500 to 3000, from 400 to 3000, from 500 to 3000, from 600 to 3000, from 700 to 3000, from 800 to 3000, from 900 to 3000, from 1000 to 3000, or from 2000 to 3000).
Numerous ERIb agonists are known in the art, and described for example in Mohler, M. L., et al“Estrogen Receptor b Selective Nonsteroidal Estrogens: Seeking Clinical Indications” Expert Opin. Ther. Patents (2010) 20(4): 507-534, which is incorporated herein by reference.
In some embodiments, the agonist can be a hydroxy-biphenyl-carbaldehyde oxime derivative. Examples of such agonists are described, for example, in U.S. Patent No.
7,279,600 to Mewshaw et al. and International Publication No. WO 2004/099122 to Mewshaw et al., each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula I below
Figure imgf000014_0001
wherein
R1 and R2, are each, independently, H, halogen, CN, substituted or unsubstituted phenyl, or substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl); R3, R4, R5 and R6, are each independently, H, OH, halogen, CN, substituted or unsubstituted phenyl, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted Ci-Ce alkyl), or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy);
R8 are each, independently H, -C(0)R9, or substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl); and
R9 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl);
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
In some embodiments, R8 is, in each case, H.
In certain embodiments, the agonist can be one of the compounds shown below.
Figure imgf000015_0001
In some embodiments, the agonist can be a naphthyl-linked carbaldehyde oxime derivative. Examples of such agonists are described, for example, in U.S. Patent No.
7,157,491 to Mewshaw et al. and International Publication No. WO 2004/103941 to Mewshaw et al., each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula II below
Figure imgf000015_0002
wherein R1 is hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy);
R2 and R3, together, form a fused aryl or heteroaryl ring;
R4 is hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy);
R5 are each, independently H, -C(0)R6, or substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl); and
R6 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl);
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
In some embodiments, R5 is, in each case, H.
In certain embodiments, the agonist can be one of the compounds shown below.
Figure imgf000016_0001
In some embodiments, the agonist can be an indole-linked carbaldehyde oxime derivative. Examples of such agonists are described, for example, in U.S. Patent No. 7,250,440 to Mewshaw et al. and International Publication No. WO 2005/018636 to Mewshaw et al., each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula III below
Figure imgf000016_0002
wherein
Ri is hydrogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), halogen, CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy) and R2 IS hydrogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), or substituted or unsubstituted phenyl; or Ri and R2 together may form a 5-7 membered ring; and
R3, and R4 are each, independently, H, OH, halogen, CN, substituted or unsubstituted phenyl, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy);
or a pharmaceutically acceptable salt or prodrug thereof.
In certain embodiments, the agonist can be one of the compounds shown below.
Figure imgf000017_0001
In some embodiments, the agonist can be defined by Formula IV below
Figure imgf000017_0002
wherein
R1 is, independently for each occurrence, H, -C(0)R4, or substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl); and
R2 is hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy);
R3 is hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy); and
R4 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl);
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
In some embodiments, R1 is, in each case, H.
In certain embodiments, the agonist can be one of the compounds shown below.
Figure imgf000018_0001
In some embodiments, the agonist can comprise 2,3-bis(4- hydroxyphenyl)propionitrile (DPN) or a derivative or analog thereof. For example, in some embodiments, the agonist can be a compound defined by Formula V below
Figure imgf000018_0002
wherein
the dashed line indicates a single bond or a double bond;
R1 is, independently for each occurrence, H, -C(0)R6, or substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl);
R2 and R3 are each, independently, H or CN;
R4 and R5 are each, independently, hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy); and
R6 is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl);
or a pharmaceutically acceptable salt thereof or a prodrug thereof.
In some embodiments, R1 is, in each case, H.
In some embodiments, the agonist can be a compound defined by the formula below
Figure imgf000018_0003
wherein R4 and R5 are each, independently, hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy). In one embodiment, R4 and R5 are each, independently, hydrogen or methyl.
In some embodiments, the agonist can be a compound defined by the formula below.
Figure imgf000019_0001
In some embodiments, the agonist can be a compound defined by the formula below
Figure imgf000019_0002
wherein R4 is hydrogen or CN.
In some embodiments, the agonist can be a sulfonamide. Examples of such agonists are described, for example, in U.S. Patent Application Publication No. 20070021495 to Katzenellenbogen et al., which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula VI below
Figure imgf000019_0003
Formula VI
or a salt, stereoisomer or prodrug thereof wherein
AR is an optionally substituted aryl group;
R3 is an alkyl, alkenyl, alkynyl, benzyl, or phenyl group;
Ri is a hydrogen, a halide, a hydroxy, thiol, an alkyl, alkenyl, alkynyl, benzyl, phenyl alkoxy, thioalkoxy, or aryloxy group; and
Xi— X4, independently of one another, are selected from the group consisting of hydrogens, halogens, alkyl groups, alkoxy groups,— CO— R groups,— SR groups, cyano groups, nitro groups, hydroxy groups, alkoxy groups, thiol groups, and thioalkoxy groups, where R is H, or an alkyl group, wherein R3 can be linked with X3, or X4 to form a 5, 6 or 7- member ring which may be an aromatic ring, or may contain one or two double bonds and wherein the ring optionally contains one or two additional heteroatoms wherein all alkyl, alkenyl, alkynyl, aryl, benzyl and phenyl groups are optional substituted and wherein optional substitution means substitution with one or more halogens, cyano groups, nitro groups, hydroxy groups, alkoxy groups, thiol groups, thioalkoxy groups, aryloxy groups, N(R)'2 groups, CON(R')2 groups or— COOR' groups, where R' is H or an alkyl group and where R' groups may be linked to form a cyclic alkyl group.
In certain embodiments, the agonist can be defined by the formula below
Figure imgf000020_0001
wherein R is substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl, such as -CH , -CH2CH2CH , -CH2CH2CH2CH , -CH(CH )(CH2CH ), - CH(CH )(CH2CH2CH ), or -CH2CH2CF ).
In some embodiments, the agonist can comprise a monocycle-linked bis-phenyl estrogenic agonist. Examples of such agonists are described, for example, in International Publication No. WO 2000/019994 to Katzenellenbogen et al., which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise a thiophene-based agonist.
Examples of such agonists are described, for example, in U.S. Patent No. 6,835,745 to Coghlan et al., which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula VII below
Figure imgf000020_0002
Formula VII
wherein
R1 is phenyl optionally substituted with 1-4 Y groups;
R2 is phenyl optionally substituted with 1-4 Y groups, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, haloalkenyl of 2-7 carbon atoms, or haloalkynyl of 2-7 carbon atoms;
R3 is hydrogen, phenyl optionally substituted with 1-4 Y groups, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, alkoxy carbonyl of 2-7 carbon atoms, alkylthio of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, haloalkenyl of 2-7 carbon atoms, or haloalkynyl of 2-7 carbon atoms;
X is O,— CH=CH— , or S;
Y is— OH,— OR4, halogen,— CN,— CO2H,— CO2R4, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, perfluoroalkyl of 1-6 carbon atoms, or— COR4;
Z is— CHO,— CN,— CO2H,— CO2R4,— CONR4R5,— NO2,— CH=NR4,—
CH=— CH=N OR4 ;
R4 and R5 are each, independently, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or cycloalkyl of 3-8 carbon atoms;
with the proviso that at least one of R2 or R3 is phenyl or phenyl substituted with 1-4 Y groups;
or a pharmaceutically acceptable salt thereof.
In some embodiments, the agonist can be a compound defined by the formula below
Figure imgf000021_0001
wherein Ris hydrogen, halogen, substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy). In one embodiment, R is hydrogen or halogen (e.g., F or Cl).
In some embodiments, the agonist can comprise a cycloalkane-linked biphenyl. Examples of such agonists are described, for example, in U.S. Patent Application
Publication No. 2005/0256210 to Olsson et ah, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula VIII below
Figure imgf000022_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
n is an integer selected from the group consisting of 3, 4, 5 and 6;
Ri is selected from the group consisting of hydrogen, Ci-Cx straight chained or branched alkyl, Ci-Cs straight chained or branched alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalicyclyl, sulphonyl, Ci-Cx straight chained or branched perhaloalkyl,
— C(=Z)Re,— C(=Z)OR6, and— C(=Z)N(R )2;
R2, R2a, R2b, R2C are separately selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl,— CN,— OR5,— NRr,Rr, ,— NReNRea sb,— NR6N=CR6a 5b,— N(R6)C(R6a)=NR6b,— C(=Z)Re,— C(=Z)ORe,— C(=Z)NR6R6a,— N(R )— C(=Z)R a,— N(Re)— C(=Z)NR6bR6a,— OC(=Z)Re,— N(Re)— S(=0)2R6a, and— SRe;
each R3 is separately selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl, hydroxy, halogen, sulfonyl, perhaloalkyl,— CN, =0, and— OR5, or are separately absent to accommodate a double bond;
two R3 groups are optionally bound together to form a substituted or unsubstituted C3- C9 cycloalkyl or C3-C9 heteroalicyclyl;
any bond represented by a dashed and solid line represents a bond selected from the group consisting of a single bond and a double bond;
R4, R4a, R4b, R4C are separately selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl, hydroxy, nitro, halogen, sulfonyl, perhaloalkyl,— ORs,— NRr,Rr,a,— NRiNRia ib,— NR6N=CR6aR6t>,— N(R6)C(R6a)=NR6b,— CN,— C(=Z)Re,— C(=Z)ORe,— C(=Z)NR6R6a,— S(=Z)NR6R6a,— N(Re)— C(=Z)R6a,— N(Re)— C(=Z)NR6bRea,— OC(=Z)R6,— N(R6)— S(=0)2R6a, and— SRe;
R4a and R4b are optionally bound together to form an aryl, heteroaryl, or heteroalicyclyl;
R5 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, halogen,— CN,— SR5, sulfonyl,— C(=0) R6R6a,— C(=0)R6,— NRr,Rr, ,
— COOR6, and perhaloalkyl;
Z is oxygen or sulfur; and
Rf„ Rsa, and R¾ are separately selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalicyclyl.
In some embodiments, the agonist can comprise a spiro indene-indene agonist. Examples of such agonists are described, for example, in International Publication No. WO 2002/091993 to Blizzard et ah, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula IX below
Figure imgf000023_0001
wherein
each X is independently selected from the group consisting of CH2, C=0, C=CH2, C=NORa, CHCH3, CHF, CHOH, C(CH )OH, CF2 and S; R1, R2, R3, R4, R6, R7, R8, R9 and R10 are each independently selected from the the group consisting of Ra, ORa, OC02Ra, NRaRa, C02Ra, CN, Cl, F and Br;
R11, R12, R13 and R14 are each independently selected from the group consisting of H, Rb, ORb, OC02Rb, NRaRb, C02Rb, F, Cl, CN, Br;
R5 is selected from the group consisting of H, F and Ci-6alkyl;
Rais selected from the group consisting of H, Ci-6alkyl and Ci-6acyl;
Rb is selected from the group consisting of C2-7alkyl and C2-7acyl, wherein said alkyl and acyl groups may be optionally substituted with an Rc group;
Rc is selected from the group consisting of ORd and NRdRe,
Rd and Re are each independently selected from the group consisting of H and Ci-
7 alkyl;
or Rd and Re can be taken together with the nitrogen atom to which they are attached to form a 4-8 membered ring, wherein said ring is optionally interrupted by one of O, NH, NCFF and S and is optionally substituted with one, two, three or four Ci-2 alkyl groups, or one or two Rf groups;
Rf is selected from the group consisting of CH2OH and CH2CH2OH;
or a pharmaceutically acceptable salt or stereoisomer thereof.
In some embodiments, the agonist can be a phenyl bicyclic agonist, such as an indenone agonist, an indene agonist, a benzofuran agonist, a benzimidazole agonist, a benzthiazole agonist, a benzoxazole agonist, a benzisoxazole agonist, an indazole agonist, an indole agonist, or a benzisothiazole agonist.
In some embodiments, the agonist can comprise an indenone agonist. Examples of such agonists are described, for example, in U.S. Patent No. 6,903,238 to McDevitt et ak, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula X below
Figure imgf000024_0001
Formula X
wherein Ri is hydrogen, hydroxyl, halogen, trifluoroalkyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6 carbon atoms, sulfonoalkyl of 1-6 carbon atoms,— CN,— NO?,— CHFCN,— CFiCN, aryl of 6-10 carbon atoms,— NR4R5,— NCOR4,— SR4,— SOR4,— SO2R4, or a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluoroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms,— COR4,— C02R4,— CONR4RS, or R4R5;
R2 is hydrogen, hydroxyl, alkyl of 1-6 carbon atoms, halogen, phenyl substituted with Ri, alkylthio of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, amino, aminoalkyl of 1-6 carbon atoms, alkylamino of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or alkenyl of 2-7 carbon atoms;
R3 is hydrogen, halogen, hydroxyl, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms;
R4 and R5 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6- 10 carbon atoms;
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the agonist can be
Figure imgf000025_0001
wherein R1 is halogen (e.g., Br), R2 is hydrogen, R3 is hydroxy, and R4 is hydrogen.
In certain embodiments, the agonist can be
Figure imgf000025_0002
wherein R1 is halogen (e.g., Br), R2 is hydroxy, R3 is hydrogen, and R4 is hydrogen.
In certain embodiments, the agonist can be wherein R1 is methyl, R2 is hydroxy, R3 is hydrogen, and R4 is hydroxy.
In some embodiments, the agonist can comprise an indene agonist. Examples of such agonists are described, for example, in International Publication No. WO 2008/043567 to Jemstedt et al. and U.S. Patent Application Publication No. 2009/0326018 to Jernstedt et ah, each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XI below
Figure imgf000026_0001
Formula XI
wherein either the bond between the Cl and C2 carbon atoms is a double bond or the bond between the C2 and C3 carbon atoms is a double bond, R2 being absent when the bond between the Cl and C2 carbon atoms is a double bond;
R1 and R2 are independently selected from the group consisting of hydrogen, ORA, Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C3-8cycloalkyl Ci-6 alkyl, C6-10 aryl, C6- loaryl Ci-6 alkyl, halogen, halo Ci-6 alkyl, dihalo Ci-6 alkyl and trihalo Ci-6 alkyl; or R1 and R2 taken together with the carbon atom to which they are attached form a double bond portion of C2-6 alkenyl group;
RA is selected from the group consisting of hydrogen, Ci-6 alkyl, C2-6 alkenyl, C2- 6 alkynyl, C3-8 cycloalkyl, C3-8 cycloalkyl Ci-6 alkyl, C6-10 aryl and C6-10 aryl Ci-6 alkyl;
R3 is selected from the group consisting of hydrogen, Ci-6 alkyl, C3-8cycloalkyl and — C(0)Ci-4 alkyl;
R4, R5, R6 and R7 are the same or are different and each is selected from the group consisting of hydrogen, ORA, halogen, cyano, nitro, Ci-6alkyl, C2-6alkenyl, C2-6 alkynyl, halo Ci-6 alkyl, dihalo Ci-6alkyl and trihalo Ci-6alkyl;
R8 is selected from the group consisting of C3-8 cycloalkyl, C3-8 cycloalkyl Ci-6 alkyl, phenyl, benzyl and C5-10 heterocyclyl wherein said phenyl, benzyl or C5-10 heterocyclyl group can either be unsubstituted or substituted with 1-3 substituents and each substituent is selected from the group consisting of ORA, halogen, cyano, nitro, Ci-6 alkyl, C2-6 alkenyl, C2-6alkynyl, halo C1.4 alkyl, dihalo Ci-6 alkyl, trihalo Ci-6 alkyl and C(0)Ci^alkyl; R10 is ORa; and
R9, R11 and R12 are the same or are different and each is selected from the group consisting of hydrogen, ORA, halogen, cyano, nitro, C i-6 alkyl, C2-6alkenyl, C2-6 alkynyl, C(0)H, C(0)Ci-6 alkyl, halo C i-6 alkyl, dihalo Ci-6 alkyl and trihalo Ci-6 alkyl;
or a pharmaceutically acceptable ester, amide, solvate or salt thereof.
In certain embodiments, the agonist can be the compound shown below.
Figure imgf000027_0001
In some embodiments, the agonist can comprise a benzofuran agonist. Examples of such agonists are described, for example, in U.S. Patent No. 6,774,248 to Miller et ah, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XII below
Figure imgf000027_0002
Formula XII
wherein
A is alkyl of 1-6 carbon atoms, halogen, trifluoroalkyl of 1-6 carbon atoms, hydroxyalkyl of 1-6 carbon atoms,— CO2H,— NFF, or— OP;
A' is— OP,— CO2P, halogen, or hydroxyalkyl;
P is hydrogen, alkyl of 1-6 carbon atoms, or phenyl;
Z is hydrogen, alkyl of 1-6 carbon atoms, halogen,— NO2,— CN, triflouroalkyl of 1-6 carbon atoms,— COP,— CO2P, or— C(P)=N— OP;
R and R' are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2- 7 carbon atoms, halogen,— OP,— SP,— SOP,— SO2P,— SCN, trifluoroalkyl of 1-6 carbon atoms,— CF2CF3, trifluoroalkoxy of 1-6 carbon atoms,— NO2,— NFF,— NHOP, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 1-6 carbon atoms per alkyl group, -alkyl - SP, -alkyl-SOP, -alkyl-S02P,— CN, -alkyl-CN, -alkenyl-CN, -alkylSCN,— CHFCN,— CF2CN, -alkenyl-N02, haloalkyl of 1-6 carbon atoms, dihaloalkenyl of 2-7 carbon atoms, —COP,— COCF3,— CO2P,— CONR1R2, -alkyl-CONRiR.2, -alkenyl-CON R1R2, -alkyl- COP, -alkenyl-COP, -alkenyl-C02P, -alkenyl-C02P, oxadiazolyl, furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, or tetrazolyl;
X and Y are each, independently, hydrogen, alkyl of 1-6 carbon atoms, halogen,— NO2,— CN, trifluoroalkyl of 1-6 carbon atoms,— OP, hydroxyalkyl of 1-6 carbon atoms,
— CO2H, or phenyl which is optionally mono- or di-substituted with hydroxyl, benzyloxy, alkoxy of 1-6 carbon atoms, or— OCH2CH2NR1R2;
Ri and R2 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or alkoxy of 1-6 carbon atoms; or Ri and R2 are concatenated together as— (CH2)P— ; p=2-6;
or a pharmaceutically acceptable salt thereof.
In one example, the agonist can be the compound shown below.
Figure imgf000028_0001
In some embodiments, the agonist can comprise a benzimidazole agonist, a benzthiazole agonist, or a benzoxazole agonist. Examples of such agonists are described, for example, in International Publication No. WO 2002/046168 to Barlaam et al.,
International Publication No. WO 2002/051821 to Barlaam et al., and International
Publication No. WO 2003/045930 to Bernstein, each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XIII below
Figure imgf000028_0002
Formula XIII
wherein
R1 is Ci-salkyl, phenyl, benzyl or a 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms each independently selected from O, N and S and additionally having 0 or 1 oxo groups and 0 or 1 fused benzo rings, wherein the Ci-salkyl, phenyl, benzyl or heterocycle is substituted by 1, 2 or 3 substituents selected from— ORa,— SRa,— NRaRa, — C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,—
NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and Ci- 3haloalkyl; and wherein the phenyl, benzyl or heterocycle is additionally substituted by 0, 1 or 2 substituents selected from Ci-6alkyl, phenyl or benzyl;
R2 is H, Ci-6alkyl,— (CH2)m phenyl,— (CH2)m naphthyl or— (CH2)m heterocycle, wherein the heterocycle is a 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms each independently selected from O, N and S and additionally having 0 or 1 oxo groups and 0 or 1 fused benzo rings, wherein the Ci-6alkyl,— (CH2)m phenyl,— (CH2)m naphthyl or— (CH2)m heterocycle are substituted with 0, 1 or 2 substituents selected from — Ra,— ORa,— SRa,— NRaRa,— C02Ra,— OC(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra, — NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and C1-3 haloalkyl;
R3 is— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— OC(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and Ci haloalkyl; or R3 is Ci.3alkyl containing 1 or 2 substituents selected from— ORa,— SRa,— NRaRa,— C02Ra,— OC(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano and nitro;
R4 is— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— OC(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro or Ci-3haloalkyl;
R5 is— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— OC(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro or C1-3 haloalkyl;
R6 is— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— OC(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and Ci haloalkyl; or R6 is Ci.3alkyl containing 1 or 2 substituents selected from— ORa,— SRa,— NRaRa,— C02Ra,— OC(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano and nitro;
Ra is H, Ci-6alkyl, Ci.3haloalkyl, phenyl or benzyl; and
m is 0, 1, 2 or 3; or a pharmaceutically acceptable salt or ester thereof.
In some embodiments, the agonist can be defined by Formula XIV below
Figure imgf000030_0001
Formula XIV
wherein:
X is O or S;
R1 is Ci-8 alkyl, phenyl, benzyl or a 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms each independently selected from O, N and S and additionally having 0 or 1 oxo groups and 0 or 1 fused benzo rings, wherein the Ci-8 alkyl, phenyl, benzyl or heterocycle is substituted by 0, 1, 2 or 3 substituents selected from— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and Ci-3 haloalkyl;
R3 is— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NR2C(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and C1-3 haloalkyl; or R3 is C1.3 alkyl containing 1 or 2 substituents selected from— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano and nitro;
R4 is— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro or C1-3 haloalkyl;
R5 is— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro or C1-3 haloalkyl;
R6 is— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and C1-3 haloalkyl; or R6 is C1.3 alkyl containing 1 or 2 substituents selected from— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano and nitro; and
Ra is H, Ci-6 alkyl, C1-3 haloalkyl, phenyl or benzyl; or
a pharmaceutically acceptable salt or ester thereof.
In some embodiments, the agonist can be defined by Formula XV below
Figure imgf000031_0001
Formula XV
wherein:
X is O or S;
R1 is Ci-8alkyl, phenyl, benzyl or a 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms each independently selected from O, N and S and additionally having 0 or 1 oxo groups and 0 or 1 fused benzo rings, wherein the Ci-salkyl, phenyl, benzyl or heterocycle is substituted by 0, 1, 2 or 3 substituents selected from— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRa(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and Ci- 3haloalkyl;
R3 is— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NRaC(0)Ra— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and Ci-3haloalkyl; or R3 is Ci.3alkyl containing 1 or 2 substituents selected from— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano and nitro;
R4 is H or— NRaRb;
R5 is H or— NRaRb; wherein R4 and R5 are not both H;
R6 is— Ra,— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRaRa, NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and Ci-3haloalkyl; or R6 is Ci.3alkyl containing 1 or 2 substituents selected from— ORa,— SRa,— NRaRa,— C02Ra,— 0C(=0)Ra,— C(=0)NRa,— NRaC(=0)Ra,— NRaS(=0)Ra,— NRaS(=0)2Ra,— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano and nitro;
Rais H, Ci-6alkyl, Ci-3haloalkyl, phenyl or benzyl; and
Rb is Ci-salkyl, Ci-8alkylC4-8cycloalkyl, C2-6alkenyl, C2-6alkenyl-Ph, C2-6alkenyl-Het, — (CH2)n-Ph or— (CH2)n-Het wherein n is 0-4 and Het is a 5- or 6-membered ring heterocycle containing 1, 2 or 3 heteroatoms each independently selected from O, N and S and additionally having 0 or 1 oxo groups and 0 or 1 fused benzo rings, wherein the Ci- 4alkyl, phenyl or heterocycle is substituted by 0, 1, 2 or 3 substituents selected from— Ra, — ORa,— SRa,— NRaRa,— C02Ra,— OC(=0)Ra,— C(=0)NRaRa,— NRaC(=0)Ra,— NRaS(=0)Ra, NRaS(=0)2Ra— C(=0)Ra,— S(=0)Ra,— S(=0)2Ra, halogen, cyano, nitro and Ci-3 haloalkyl;
or a pharmaceutically acceptable salt or ester thereof.
In certain embodiments, the agonist can be the compound shown below.
Figure imgf000032_0001
In some embodiments, the agonist can comprise a naphthyl-benzoxazole agonist or a benzoxazole agonist. Examples of such agonists are described, for example, in U.S. Patent No. 6,960,607 to Malamas et al. and U.S. Patent No. 6,794,403 to Malamas et ah, each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XVI below
Figure imgf000032_0002
Formula XVI
wherein
A is one of the groups shown below
Figure imgf000033_0001
R1, R3, and R4 are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms,—COR5,— C02R5,— N02, CONR5R6, NR5R6 or N(R5)COR6;
R2 is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, triflouroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6 carbon atoms, sulfonoalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, a 5 or 6-membered
heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S,— N02,— NR5R5,— N(R5)COR6,— CN,— CHFCN,— CF2CN, alkynyl of 2-7 carbon atoms, or alkenyl of 2-7 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluroalkyl, trifluoroalkoxy,— COR5,— CO2R5,— NO?, CONR5R5, NR5R5 or N(R5)CORe;
R5 and R6 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, aryl of 6-10 carbon atoms,— CN,— CHFCN, or— CF2CN; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluroalkyl of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms,— COR7,— C02R7,— NO?,
C0NR7R8, NR7R8 or N(R7)COR8;
R7 and R8 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6- 10 carbon atoms;
X is O, S, or NR9;
R9 is hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, COR5, C02R5, or S02R5;
or a pharmaceutically acceptable salt or ester thereof.
In some embodiments, the agonist can be defined by Formula XVII below
Figure imgf000034_0001
wherein
Ri is hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, triflouroalkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoroalkoxy of 1-6 carbon atoms, thioalkyl of 1-6 carbon atoms, sulfoxoalkyl of 1-6 carbon atoms, sulfonoalkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, a 5 or 6-membered heterocyclic ring having 1 to 4 heteroatoms selected from O, N or S,— NO2,— NR Rr,,— N(R5)COR6,— CN,— CHFCN,— CF2CN, alkynyl of 2-7 carbon atoms, or alkenyl of 2-7 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluoroalkyl, trifluoroalkoxy,— COR5,— CO2R5,— NO2, CONR5R5, NR5R5 or N(R5)COR6;
R2 and R2a are each, independently, hydrogen, hydroxyl, halogen, alkyl of 1-6 carbon atoms, alkoxy of 1-4 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluoroalkyl, trifluoroalkoxy,— COR5,— CO2R5,— NO2, CONR5R5, NR5R5 or
N(R5)COR6;
R3, R3a, and R4 are each, independently, hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, halogen, alkoxy of 1-4 carbon atoms, trifluoroalkyl of 1-6 carbon atoms, or trifluoroalkoxy of 1-6 carbon atoms; wherein the alkyl or alkenyl moieties are optionally substituted with hydroxyl,— CN, halogen, trifluoroalkyl, trifluoroalkoxy,— COR5,— CO2R5,— NO2, CONR5R5, NR5R5 or
N(R5)COR6;
R5, Rr, are each, independently hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms;
X is O, S, or NR7; and
R7 IS hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms,— COR5,— CO2R5 or— SO2R5; or a pharmaceutically acceptable salt or ester thereof.
In certain embodiments, the agonist can be one of the compounds shown below.
Figure imgf000035_0001
In some embodiments, the agonist can comprise a benzimidazole agonist. Examples of such agonists are described, for example, in U.S. Patent Application Publication No. 2004/0002524 to Chesworth et af, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XVIII below
Figure imgf000035_0002
Formula XVIII
or a pharmaceutically acceptable salt or ester thereof; wherein
R 1 and R2 are each independently selected from the group consisting of (Ci-
C6)alkyl; phenyl; (C2-C6)heteroaryl; (C3-C8)cycloalkyl; and (C4-C8)cycloalkenyl, wherein the (C i-C6)alkyl; phenyl; (C2-C6)heteroaryl; (C3-C8)cycloalkyl; or (C4-C8)cycloalkenyl groups of R1 or R2 are optionally substituted by from 1 to 3 substituents independently selected from the group consisting of halogen; (C i-C6)alkyl; (C3-C8)cycloalkyl; (C4-
C8)cycloalkenyl; (Ci-C6)alkoxy; hydroxy; R12 CO2, R12R13NCO, R12R13N; (Ci-
C6)alkylcarbonyl,— CHO, cyano, thio; (Ci-C6)alkylthio; (Ci-C6)alkylsulfonyl; (Ci-
C6)alkylsulfmyl; hydroxy(Ci-C6)alkyl; (Ci-C6)alkoxycarbonylamino; (Ci-
C6)alkylcarbonylamino; (Ci-C6)alkenylcarbonylamino; (Ci-C6)alkoxycarbonyloxy;
R12R13N(CI-C6); R12R13N(Ci-C6)alkoxy; R12R13N(Ci-C6alkyl)S; N-morpholino(CH2)nO; or
— R12R13N(CH2)nS(0)x; wherein the (Ci-Ce)alkyl; (C3-C8)cycloalkyl; (C4-C8)cycloalkenyl;
(Ci-C6)alkoxy; (Ci-C6)alkylcarbonyl; (Ci-C6)alkylthio; (Ci-C6)alkylsulfonyl; (Ci-
C6)alkylsulfmyl; (Ci-C6)alkoxycarbonylamino; (Ci-C6)alkylcarbonylamino; (Ci-
C6)alkenylcarbonylamino; or (Ci-C6)alkoxycarbonyloxy groups are each optionally further substituted by from 1 to 3 substituents independently selected from the group consisting of halogen, (C i-Ce)alkyl; (C3-C8)cycloalkyl; (C4-C8)cycloalkenyl; (Ci-C6)alkoxy, hydroxy, R12 C02, R12R13NCO, R12R13N;(Ci-C6)alkylcarbonyl,— CHO, cyano, thio; R12S02(Ci- C6)alkyl; R12 C02(Ci-C6)alkyl; R12R13NCO(Ci-C6)alkyl; R12 CO(Ci-C6)alkyl; R12 S02(Ci- C6)alkoxy; R12 C02(Ci-C6)alkoxy; R12R13NCO(Ci-C6)alkoxy; R12CO(Ci-C6)alkoxy;
R12R13 N S02(Ci-C6)alkyl; and R12R13N S02(Ci-C6) alkoxy; wherein R 12 and R13 are each independently selected from the group consisting of hydrogen; (Ci-Cv)alkyl; (C3-
C8)cycloalkyl; (C4-C8)cycloalkenyl;(C6-Cio) aryl; (C2-Cio)alkenyl, (C2-Cio)alkynyl; (C2- C4)heteroaryl; (Ci-Ce)alkylaryl; (Ci-Ce) alkyl(C2-C6)heteroaryl; (C2-Ce)alkoxyaryl; (C2-Ce) alkoxy(C2-C6)heteroaryl; or R12 and R13 taken together form a three to eight membered heterocyclic ring having 1 to 3 heteroatoms; n is from 0 to 5; and x is 1 or 2;
or R 1 and R2 are each independently a group of the Formula A:
Figure imgf000036_0001
Formula A
wherein R 7, R8, R10 and R11 are each independently hydrogen; hydroxy; (Ci-Ce) alkyl; (Ci- C6)alkoxy; or halogen;
R 9 is hydroxy; (Ci-Ce) alkoxy; (Ci-C6)alkoxycarbonyloxy; (Ci- C6)alkylcarbonyloxy; (C3-C8)cycloalkoxy; (C4-C8)cycloalkenyloxy; or (C6-C12) aryloxy; and
R3, R4, R5 and R6 are each independently hydrogen, hydroxy; (Ci-Ce)alkyl; (Ci- C6)alkoxy, or halogen;
with the proviso that at least one of R1 or R2 must be the group of Formula A.
In some embodiments, the agonist can be one of the compounds below.
Figure imgf000036_0002
In some embodiments, the agonist can be an indazole agonist, such as the compound shown below.
Figure imgf000037_0001
In some embodiments, the agonist can comprise an indole agonist. Examples of such agonists are described, for example, in Japanese Patent Application Publication No. JP2001122855 to Fujii et al., and U.S. Patent Application Publication No. 2003/0220377 to Chesworth, each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XIX below
Figure imgf000037_0002
Formula XIX
or a pharmaceutically acceptable salt or ester thereof; wherein
R 1 and R2 are each independently selected from the group consisting of (Ci- C6)alkyl; phenyl; (C2-C6)heteroaryl; (C3-C8)cycloalkyl; and (C4-C8)cycloalkenyl; wherein the (C i-C6)alkyl; phenyl; (C2-C6)heteroaryl; (C3-C8)cycloalkyl; or (C -Cs) cycloalkenyl groups of R1 or R2 are optionally substituted by from 1 to 3 substituents independently selected from the group consisting of halogen; (C i-C6)alkyl; (C3-C8)cycloalkyl; (C4- C8)cycloalkenyl; (Ci-C6)alkoxy; hydroxy; R12 CO2, R12R13NCO, R12R13N; (Ci-C6) alkylcarbonyl,— CHO, cyano, thio; (Ci-C6)alkylthio; (Ci-C6)alkylsulfonyl; (Ci- C6)alkylsulfmyl; hydroxy(Ci-C6)alkyl; (Ci-C6)alkoxycarbonylamino; (Ci- C6)alkylcarbonylamino; (Ci-C6)alkenylcarbonylamino; (Ci-C6)alkoxycarbonyloxy;
R12R13N(CI-C6); R12R13N(Ci-C6)alkoxy; R12R13N(Ci-C6)alkyl)S; N-morpholino(CH2)nO; or — R12R13N(CH2)nS(0)x; wherein the (Ci-Ce)alkyl; (C3-C8)cycloalkyl; (C4-C8)cycloalkenyl; (Ci-C6)alkoxy; (Ci-C6)alkylcarbonyl; (Ci-C6)alkylthio; (Ci-C6)alkylsulfonyl; (Ci- C6)alkylsulfmyl; (Ci-C6)alkoxycarbonylamino; (Ci-C6)alkylcarbonylamino; (Ci- C6)alkenylcarbonylamino; or (Ci-C6)alkoxycarbonyloxy groups are each optionally further substituted by from 1 to 3 substituents independently selected from the group consisting of halogen, (C i-Ce)alkyl; (C3-C8)cycloalkyl; (C4-C8)cycloalkenyl; (Ci-C6)alkoxy, hydroxy, R12C02, R12R13NCO, R12R13N;(Ci-C6)alkylcarbonyl,—CHO, cyano, thio; R12S02(Ci- C6)alkyl; R12C02(Ci-C6)alkyl; R12R13NCO(Ci-C6)alkyl; R12CO(Ci-C6)alkyl; R12S02(Ci- C6)alkoxy; R12C02(Ci-C6)alkoxy; R12R13NCO(Ci-C6)alkoxy; Ri2CO(Ci-C6)alkoxy;
R12R13N S02(Ci-C6)alkyl; and R12R13N S02(Ci-C6) alkoxy, wherein R 12 and R13 are each independently selected from the group consisting of hydrogen; halogen; (Ci-Cv)alkyl; (C3- C8)cycloalkyl; (C4-C8)cycloalkenyl; (C6-C10) aryl; (C2-Cio)alkenyl, (C2-Cio)alkynyl; (C2- C4)heteroaryl; (Ci-C6)alkylaryl; (Ci-C6)alkyl (C2-C6)heteroaryl; (C2-C6)alkoxyaryl; (C2-Ce) alkoxy(C2-C6)heteroaryl; or R12 and R13 taken together form a three to eight membered heterocyclic ring having up to 3 heteroatoms; n is from 0 to 5; and x is 1 or 2;
or R 1 and R2 are each independently a group of the Formula A
Figure imgf000038_0001
wherein R8, R9, R11 and R12 are each independently hydrogen; hydroxy; (Ci-
C6)alkyl; (Ci-C6)alkoxy; or halogen;
R10 is hydrogen; hydroxy; (Ci-C6)alkoxy; (Ci-C6)alkoxycarbonyloxy; (Ci- C6)alkylcarbonyloxy; (C3-C8)cycloalkoxy; (C4-C8)cycloalkenyloxy; or (C6-Ci2) aryloxy;
R3, R4, R5 and R6 are each independently hydrogen, hydroxy; (Ci-Ce)alkyl; (Ci- C6)alkoxy; or halogen; and
R7 is H or (Ci-C3)alkyl;
with the proviso that at least one of R 1 or R2 must be the group of Formula A.
In certain embodiments, the agonist can be a compound shown below.
Figure imgf000038_0002
In some embodiments, the agonist can comprise an indazole agonist, a
benzisoxazole agonist, or a benzisothi azole agonist. Examples of such agonists are described, for example, in International Publication No. WO 2006/040351 to Rondot et al., which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XX below
Figure imgf000039_0001
Formula XX
or a pharmaceutically acceptable salt or ester thereof, wherein:
Ri is hydrogen or a (Ci-C6)alkyl, (C3-C6)cycloalkyl, trifluoromethyl,— N=CRsRr,, — SO2NR7R8, phenyl, phenyl(Ci-C3)alkyl or (Ci-C3)alkyl substituted by a saturated heterocyclic radical, wherein the phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C3)alkyl, a (Ci-C3)alkoxy and a trifluoromethyl; Ri can also be a salt;
R2 and R3 are each independently hydrogen or a hydroxyl, halogen, nitro, cyano, (Ci-C6)alkyl, (C3-C6)cycloalkyl, (Ci-C6)alkoxy, trifluoromethyl,— NR-Rx,— CONR7R8,— COR9 or— CO2R9 group; R2 can also be a phenyl or a saturated or unsaturated heterocycle, wherein the phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C3)alkyl, a (Ci- C3)alkoxy, a trifluoromethyl and a saturated heterocyclic radical;
X is O, S, SO, S02 or NR4;
R4 IS hydrogen or a (Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, phenyl(Ci-C3)alkyl, (Ci-C3)alkyl substituted by a saturated heterocyclic radical,— COR7,— CO2R7 or— SO2NR7R8 group, wherein the phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C3)alkyl, a (Ci-C3)alkoxy, a trifluoromethyl, a phenyl(Ci-C3)alkyl and a phenyl(Ci- C3)alkoxy;
Y is direct bond, O, S, SO, SO2, NR4, CO,— (CRioRn)n— or— RioC=CRn— ;
R5, Rs, R7 and Rx are each independently hydrogen or a (Ci-C6)alkyl or (C3- C6)cycloalkyl group; Jig is hydrogen, a (Ci-C6)alkyl, a phenyl or a saturated or unsaturated heterocyclic radical, wherein the phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C3)alkyl, a (Ci-C3)alkoxy, a trifluoromethyl and a saturated heterocyclic radical;
Rio and Rn are each independently hydrogen or a cyano, (Ci-C6)alkyl,— CO- phenyl,— CO(unsaturated heterocyclic radical) or— CONR7R8 group, wherein the phenyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C3)alkyl, a (Ci-C3)alkoxy and a
trifluoromethyl;
n is 1 or 2; and
A is a (C3-Ci5)cycloalkyl, a (C3-Ci5)cycloalkene, a phenyl or a naphthyl, wherein the cycloalkyl or the cycloalkene is unsubstituted or substituted by at least one (Ci-C6)alkyl, and wherein the phenyl or the naphthyl is unsubstituted or substituted by at least one substituent selected from the group consisting of a hydroxyl, a halogen, a nitro, a cyano, a (Ci-C3)alkyl, a (Ci-C3)alkoxy and a trifluoromethyl;
wherein when X is NR4, Y and R2 together with the indazole ring bearing them can also form a lH-pyrano[4,3,2-cd]indazole.
In one embodiment, the agonist can be a compound shown below.
Figure imgf000040_0001
In some embodiments, the agonist can comprise a bicyclic benzopyran agonist. Examples of such agonists are described, for example, in International Publication No. WO 2003/074044 to Lugar et ah, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XXI below
Figure imgf000040_0002
wherein R1, R2, R3, and R4, are each independently hydrogen, substituted or unsubstituted alkyl, hydroxy, substituted or unsubstituted alkoxy, halogen, or -CF3; and
R5 and R6 are each independently hydrogen or substituted or unsubstituted alkyl; or a pharmaceutically salt thereof.
In certain embodiments, the agonist can be one of the compounds shown below.
Figure imgf000041_0001
In some embodiments, the agonist can comprise a 3-alkyl-4-benzylchromane agonist. Examples of such agonists are described, for example, in U.S. Patent Application Publication No. 2003/0069303 to Veeneman et ah, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XXII below
Figure imgf000041_0002
Formula XXII
or a pharmaceutically acceptable salt or ester thereof, wherein
R1 is (lC-4C)alkyl, (2C-4C)alkenyl or (2C-4C)alkynyl, and independently R1 has a cis-orientation in relation to the exocyclic phenyl group at the 2-position of the skeleton;
R4 is halogen, -CF3, OH or (lC-2C)alkyloxy; and R2, R3, and R5 are independently H, halogen, -CF3, (lC-4C)alkyl, (2C-4C)alkenyl, or (2C-4C)alkynyl.
In some embodiments, the agonist can comprise a compound described in
International Publication No. WO 2009/002802 to Cohen, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XXIII below
Figure imgf000042_0001
Formula XXIII
wherein
X is an asymmetric carbon atom having an S or R configuration;
Ri is selected from the group consisting of H and OR4; and
R2, R3, and R4 are independently selected from the group consisting of H, and glycoside, glucuronide, acyl, phosphate, phosphonic acid, alkyl phosphonate, sulfate, Ci to C6 alkyl, C3 to C6 cycloalkyl, aryl, carbonate, and carbamate; each optionally substituted with from one to three groups selected from hydrogen, Ci to C6 alkyl, phenyl, benzyl, alkylphenyl, hydroxy, alkoxy, acyloxy, amino, carboxy and alkoxycarbonyl;
or a pharmaceutically acceptable salt, or prodrug thereof.
In certain embodiments, the agonist can be the compound defined below.
Figure imgf000042_0002
In some embodiments, the agonist can comprise a compound described in
International Publication No. WO 2007/053915 to Keukeleire et ah, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XXIV below
Figure imgf000043_0001
Formula XXIV
or any stereoisomer, tautomer, solvate or pharmaceutically acceptable salt thereof, wherein the dotted line represents optionally a double bond;
Ri, Re, R9, and Rio are independently selected from OH, H, halogen, cyano, amino, nitro, nitroso, C1-5 alkyl, C1-5 alkoxy, C1-5 alkylcarbonyloxy; wherein each of said alkyl, alkoxy or alkylcarbonyloxy group is linear or branched;
R2 is selected from a branched C5 alkyl, a C6-20 alkyl, C6-20 alkenyl, C6-20 alkynyl or C6-20 alkenynyl, wherein each of said C6-20 alkyl, alkenyl, alkynyl or alkenynyl group is linear or branched;
R3, R4, R5, Rs and R7 are independently selected from OH, H, halogen, cyano, amino, nitro or nitroso;
Xi is selected from O, S;
X2 is selected from O, S or the two bonds are each separately formed with a hydrogen atom, wherein said naringenin derivative is not 8-geranylnaringenin.
In some embodiments, the agonist can comprise a chroman-7-ol agonist. Examples of such agonists are described, for example, in U.S. Patent No. 7,396,855 to Setchell et ah, and U.S. Patent No. 7,528,267 to Setchell et ah, each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise a tetrahydroisoquinoline agonist. Examples of such agonists are described, for example, in U.S. Patent No. 6,686,351 to Bhagwat et ah, and U.S. Patent No. 7,256,201 to Barlaam et ah, each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise a quinazoline or quinazolinone agonist. Examples of such agonists are described, for example, in U.S. Patent No.
7,381,730 and International Publication No. WO 2006/116401, each of which is hereby incorporated by reference in its entirety. In some embodiments, the agonist can comprise a 3-arylhydroxybenzoxazine agonist. Examples of such agonists are described, for example, in U.S. Patent No.
7,015,219, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise a 2-arylquinoline agonist.
Examples of such agonists are described, for example, in U.S. Patent Application
Publication No. 2005/0009784, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise a 2-phenylnaphthalene agonist. Examples of such agonists are described, for example, in U.S. Patent No. 6,914,074, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise a phenylnaphthalene agonist. Examples of such agonists are described, for example, in U.S. Patent Application
Publication No. 2007/0225330, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise an isoquinolinone agonist.
Examples of such agonists are described, for example, in International Publication No. 2008/091555 to Dalton et al., which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XXV below
Figure imgf000044_0001
Formula XXV
wherein
Figure imgf000044_0002
or A is nothing, N forms a double bond with the cyclic carbon and X is OH or OCH2CH2-heterocycle in which the heterocycle is a 3-7 member saturated or unsaturated, substituted or unsubstituted heterocyclic ring;
Ri, R2, and R3 are independently hydrogen, aldehyde, COOH, -C(=NH)-OH, CHNOH, CH=CHC02H, CH=CHC02R, -CH=CH2, hydroxyalkyl, halogen, hydroxyl, alkoxy, cyano, nitro, CF , NH2, 4-Ph- OMe, 4-Ph-OH, SH, COR, COOR, OCOR, alkenyl, allyl, 2-methylallyl, alkynyl, propargyl, OSO2CF3, OSO2CH3, NHR, NHCOR, N(R)2, sulfonamide, SO2R, alkyl, haloalkyl, aryl, phenyl, benzyl, protected hydroxyl, OCH2CH2NR4R5, Z-Alkyl-Q, Z-Alkyl-NR4R5, Z-Alkyl-heterocycle or OCH2CH2- heterocycle in which the heterocycle is a 3-7 member saturated or unsaturated, substituted or unsubstituted heterocyclic ring;
R is alkyl, hydrogen, haloalkyl, dihaloalkyl, trihaloalkyl, CH2F, CHF2, CF3, CF2CF3, aryl, phenyl, benzyl, -PI1-CF3, -Ph-CH2F, -Ph-CHF2, -Ph-CF2CF3, halogen, alkenyl, CN, NO2 or OH;
R1 is hydrogen, alkyl, or -COR;
R" is hydrogen, alkyl, or -COR;
R4 and R5 are independently hydrogen, phenyl, benzyl, an alkyl group of 1 to 6 carbon atoms, a 3 to 7 member cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; Z is
Figure imgf000045_0001
Q is SO3H, CO2H, CO2R, NO2, tetrazole, SO2NH2 or SO2NHR;
n is an integer between 1-3;
m is an integer between 1-2;
p is an integer between 1-4; and
Alkyl is a linear alkyl of 1-7 carbons, branched alkyl of 1-7 carbons, or cyclic alkyl of 3-8 carbons.
In some embodiments, the agonist can comprise a benzopyran agonist or a tetralin agonist. Examples of such agonists are described, for example, in U.S. Patent No.
6,630,508, International Publication No. WO 2004/094400, U.S. Patent No. 7,279,499, and International Publication No. WO 2006/088716 to Krishnan et ak, each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XXVI below
Figure imgf000045_0002
wherein
X is CH or O;
Ri, R2, and R3 are independent hydrogen, halogen (e.g., F), substituted or unsubstituted alkyl (e.g., substituted or unsubstituted C1-C6 alkyl), -CF3, CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy). In some embodiments, the agonist can be defined by Formula XXVII below
Figure imgf000046_0001
wherein
G is -CH2-, -CH2CH2-, -CH2C(CH )2- or -0-;
R1 is hydrogen, hydroxy or amino;
R2 is hydrogen or hydroxy;
R3 is hydrogen, hydroxy, Br, methyl, n-propyl, i-propyl, n-butyl, hydroxymethyl, methoxy, CH3CH(OH)-, acetyl, CH OCH2-, R7C(0)CH2CH2- Or R8CH2CH2CH2-; or R2 and R3 form a -CH2CH2-X-O- biradical, wherein the oxygen radical represents the R2 end and the methylene radical represents the R3 end;
X is -C(O)- or -C(C=CH2)-;
R4 is hydrogen, hydroxy, cyano, R9-CH2-, vinyl, 4-chlorophenyl, carboxy, aminocarbonyl or methoxycarbonyl;
R5 is hydrogen, methyl, ethyl, R10-CH2-, CH3CH(OH)-, acetyl, carboxyl or methoxycarbonyl;
R6 is hydrogen or fluoro;
R7 is amino, methylamino, dimethylamino or piperidin-l-yl;
R8 is bromo, hydroxy, dimethylamino or methoxy;
R9 is bromo, cyano, hydroxy, methoxy or azido;
R10 is bromo, hydroxy, cyano, methoxy or pyrrolidin-l-yl;
with the provisos that: at least one or R1, R2, R3 and R4 is hydroxy and at least three of R1, R2, R3, R4 and R5 are hydrogen;
and enantiomers thereof.
In some embodiments, the agonist can be defined by Formula XXVIII or Formula XXIX below
Figure imgf000047_0001
Formula XXVIII Formula XXIX wherein
X is CH or O; and
R3 are independent hydrogen, halogen (e.g., F), substituted or unsubstituted alkyl
(e.g., substituted or unsubstituted C1-C6 alkyl), -CF3, CN, or substituted or unsubstituted alkoxy (e.g., substituted or unsubstituted C1-C6 alkoxy).
In some embodiments, the agonist can comprise a tri- or tetracyclic
tetrahydrofluorene agonist. Examples of such agonists are described, for example, in U.S. Patent No. 7,157,604, U.S. Patent No. 7,087,599, International Publication No. WO
2002/041835, International Publication No. WO 2006/062876, International Publication No. WO 2007/089291, and U.S. Patent No. 7,151,196, each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XXX below
Figure imgf000047_0002
Formula XXX
wherein
X is selected from the group consisting of: O, N— ORa, N— NRaRband Ci- 6 alkylidene, wherein said alkylidene group is unsubstituted or substituted with a group selected from hydroxy, amino, 0(Ci-4alkyl), NH(Ci-4alkyl), or N(Ci-4alkyl)2;
Rx is selected from the group consisting of hydrogen, Ci-6alkyl, C2-6alkenyl, and C2- 6alkynyl, wherein said alkyl, alkenyl and alkynyl groups are either unsubstituted or substituted with a group selected from ORc, SRC, NRbRc, C(=0)Rc, C(=0)CH20H, or phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci-4alkyl, OH, 0(Ci- 4alkyl), NH2, NH(Ci-4alkyl), N(Ci-4alkyl)2, halo, CN, N02, C02H, C02(Ci-4alkyl), C(0)H, and C(0)(Ci-4alkyl);
R2 is selected from the group consisting of hydrogen, hydroxy, iodo, 0(C=0)Rc, C(=0)Rc, C02Rc, Ci-6alkyl, C2-6alkenyl, and C2-6alkynyl, wherein said alkyl, alkenyl and alkynyl groups are either unsubstituted or substituted with a group selected from ORc, SRC, NRbRc, C(=0)Rc, C(=0)CH2OH, or phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci-4alkyl, OH, 0(Ci-4alkyl), NH2, NH(Ci-4alkyl), N(Ci-4alkyl)2, halo, CN, N02, C02H, C02(Ci-4alkyl), C(0)H, and C(0)(Ci-4alkyl);
or R1 and R2, when taken together with the carbon atom to which they are attached, form a carbonyl group;
or R1 and R2, when taken together, form a Ci-6alkylidene group, wherein said alkylidene group is either unsubstituted or substituted with a group selected from the group consisting of hydroxy, 0(Ci-4alkyl), N(Ci-4alkyl)2, and phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci-4alkyl, OH, 0(Ci-4alkyl), NH2, NH(Ci-4alkyl), NH(Ci-4alkyl)2, halo, CN, N02, C02H, C02(Ci-4alkyl), C(0)H, and C(0)(Ci-4alkyl);
R3 is selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, cyano, nitro, NRaRc, ORa, C(=0)Ra, C02Rc, CONRaRc, SRa, S(=0)Ra, S02Ra, Ci-ioalkyl, C2-ioalkenyl, C2-ioalkynyl, C3-7cycloalkyl, Cs-vcycloalkenyl, 4-7 membered
heterocycloalkyl, (cycloalkyl)alkyl, (cycloalkenyl)alkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, arylalkyl, and (heteroaryl)alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl and heteroaryl groups are either unsubstituted or independently substituted with 1, 2 or 3 groups selected from fluoro, chloro, bromo, iodo, cyano, oxo, ORa, NRaRc, 0(C=0)Ra, 0(C=0)NRaRc, NRa(C=0)Rc, NRa(C=0)ORc, C(=0)Ra, C02Ra, CONRaRc, CSNRaRc, SRa, S(0)Ra, S02Ra, S02NRaRc, YRd, and ZYRd;
R4 and R5 are each independently selected from the group consisting of hydrogen, hydroxy, amino, methyl, CF3, fluoro, chloro, and bromo;
R6 is selected from the group consisting of NH2, NH(C=0)Re, and NH(C=0)ORe;
R7 is selected from the group consisting of hydrogen, ORb, NRbRc, fluoro, chloro, bromo, iodo, cyano, nitro, Ci-6alkyl, C2-6alenyl, CF3, and CBF2; R8 and R9 are each independently selected from the group consisting of hydrogen, fluoro, chloro, Ci-6alkyl, C2-6alkenyl, and C2-6alkynyl,
or R8 and R9, when taken together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl ring,
or R8 and R9, when taken together with the carbon atom to which they are attached, form a carbonyl group;
R10 is selected from the group consisting of hydrogen, Ci-ioalkyl, C2-ioalkenyl, C2- loalkynyl, C3-6cycloalkyl, C4-6cycloalkenyl, (cycloalkyl)alkyl, (cycloalkyl)alkenyl,
(cycloalkenyl)alkyl, aryl, heteroaryl, arylalkyl and (heteroaryl)alkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, (cycloalkyl)alkyl, (cycloalkyl)alkenyl,
(cycloalkenyl)alkyl, aryl, heteroaryl, arylalkyl and (heteroaryl)alkyl groups can be optionally substituted with a group selected from bromo, iodo, ORb, SRb, C(=0)Rb, 1-3 Ci- 3alkyl, 1-3 chloro, or 1-5 fluoro,
or R10 and R1, when taken together with the three intervening carbon atoms to which they are attached, form a 5-6 membered cycloalkyl or cycloalkenyl ring which can be optionally substituted with 1-3 groups independently selected from oxo, hydroxy, fluoro, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci^alkylidenyl, C3-6cycloalkyl, (cycloalkyl)alkyl, phenyl, or phenylalkyl, wherein said alkyl, alkenyl, alkynyl, alkylidenyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, and phenylalkyl groups can be optionally substituted with a group selected from chloro, bromo, iodo, ORb, SRb, Ci-3alkyl, C(=0)Rb, or 1-5 fluoro;
Rais selected from the group consisting of hydrogen, Ci-ioalkyl, and phenyl, wherein said alkyl group can be optionally substituted with a group selected from hydroxy, amino, 0(Ci-4alkyl), NH(Ci-4alkyl), N(Ci-4alkyl)2, phenyl, or 1-5 fluoro, and wherein said phenyl groups can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci-4alkyl, OH, 0(Ci-4alkyl), NH2, NH(Ci-4alkyl), N(Ci-4alkyl)2, halo, CN, N02, C02H, C02(Ci.4alkyl), C(0)H, and C(0)(Ci-4alkyl);
Rb is selected from the group consisting of hydrogen, Ci-ioalkyl, benzyl and phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci-4alkyl, OH, 0(Ci-4alkyl), NH2, NH(Ci.4alkyl), N(Ci.4alkyl)2, halo, CN, N02, C02H, C02(Ci.4alkyl), C(0)H, and C(0)(Ci- 4alkyl);
Rc is selected from the group consisting of hydrogen, Ci-ioalkyl and phenyl, wherein said phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci-4alkyl, OH, 0(Ci-4alkyl), NH2, NH(Ci.4alkyl), N(Ci.4alkyl)2, halo, CN, N02, C02H, C02(Ci-4alkyl), C(0)H, and C(0)(Ci- 4alkyl);
or Ra and Rc, whether or not on the same atom, can be taken together with any attached and intervening atoms to form a 4-7 membered ring;
Rdis selected from the group consisting of NRbRc, ORa, C02Ra, 0(C=0)Ra, CN, NRc(C=0)Rb, CONRaRc, S02NRaRc, and a 4-9 membered mono- or bi-cyclic N- heterocycloalkyl ring that can be optonally substituted with 1-3 Ci-3alkyl and can be optionally interrupted by O, S, NRC, or C=0;
Re is selected from the group consisting of hydrogen, Ci-6alkyl, C2-6alkenyl, phenyl, and phenylalkyl, wherein said alkyl, alkenyl, or phenyl group can either be unsubstituted or substituted with 1-3 substituents independently selected from the group consisting of Ci- salkyl, OH, 0(Ci-4alkyl), NH2, NH(Ci-4alkyl), N(Ci-4alkyl)2, halo, CN, N02, C02H, C02(Ci-4alkyl), C(0)H, and C(0)(Ci-4alkyl);
Y is selected from the group consisting of CRbRc, C2-6alkylene and C2-6alkenylene, wherein said alkylene and alkenylene linkers can be optionally interrupted by O, S, or NRC; and
Z is selected from the group consisting of O, S, NRC, C=0, 0(C=0), (C=0)0, NRc(C=0) or (C=0)NRc;
or pharmaceutically acceptable salt or ester thereof.
In some embodiments, the agonist can comprise a pyranoflavonoid agonist.
Examples of such agonists are described, for example, in International Publication No. WO 2002/058639, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise a dibenzochromene agonist.
Examples of such agonists are described, for example, in U.S. Patent No. 7, 157,492 to Mewshaw et al. and International Publication No. WO 2003/051863 to Mewshaw et ah, each of which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise a 6H-chromeno[4,3-b]quinoline agonist. Examples of such agonists are described, for example, in U.S. Patent Application Publication No. 2006/0052410 to Vu et al., which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise a tetracycle containing benzofuran. Examples of such agonists are described, for example, in U.S. Patent Application Publication No. 2006/0004087 to Miller et al., which is hereby incorporated by reference in its entirety. In one example, the agonist can comprise WAY-358.
In some embodiments, the agonist can comprise a cycloalkyl-substituted benzopyran. Examples of such agonists are described, for example, in International Publication No. WO 2004/094400 to Durst et al., which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XXXI below
Figure imgf000051_0001
Formula XXXI
wherein
G is CHCi-Ce alkyl, C=0, CHOH, CF2, C(OH)CF , CHCF3, CH(OH)Ci-C6alkyl, CH— OCi-Cealkyl, CH— 0(CO)Ci-C6alkyl, CHF, CHCN, CHC2-C4alkenyl, CHC2- C4alkynyl, CHbenzyl, difluoromethylene, O, or S(0)n, wherein n is 0-2;
including enantiomers thereof and pharmaceutically acceptable salts thereof.
In some embodiments, the agonist can comprise one or more of the following: (a) (2S, 3aS, 4R, 9bR)-4-(4-Hydroxy-phenyl)-2-methyl-l,2,3,3a,4,9b-hexahydro- cyclopenta[c]chromen-8-ol; (b) (2R, 3aR, 4S, 9bS)-4-(4-Hydroxy-phenyl)-2-methyl- l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (c) (2R, 3aR, 4S, 9bS)-2-tert-Butyl-4- (4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (d) (2S, 3aS, 4R, 9bR)-2-tert-Butyl-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8- ol; (e) (3aS, 4S, 9bS)-4-(4-Hydroxy-phenyl)-l,3a,4,9b-tetrahydro-3H-2,5-dioxa- cyclopenta[a]naphthalen-8-ol; (f) (3aR, 4R, 9bR)-4-(4-Hydroxy-phenyl)-l,3a,4,9b- tetrahydro-3H-2,5-dioxa-cyclopenta[a]naphthalen-8-ol; (g) (3aR, 4S, 9bS)-4-(4-Hydroxy- phenyl)-l,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol; (h) (3aS, 4R, 9bR)-4-(4-Hydroxy-phenyl)-l,3a,4,9b-tetrahydro-3H-5-oxa-2-thia- cyclopenta[a]naphthalen-8-ol; (i) (2S, 3aR, 4S, 9bS)-4-(4-Hydroxy-phenyl)-2-oxo- l,2,3,3a,4,9b-hexahydro-5-oxa-2k4-thia-cyclopenta[a]naphthalen-8-ol; (j) (2R, 3aS, 4R, 9bR)-4-(4-Hydroxy-phenyl)-2-oxo-l,2,3,3a,4,9b-hexahydro-5-oxa-2k4-thia- cyclopenta[a]naphthalen-8-ol; (k) (3aR, 4S, 9bS)-4-(4-Hydroxy-phenyl)-2,2-dioxo- 1 ,2,3,3a,4,9b-hexahydro-5-oxa-2k -thia-cyclopenta[a]naphthalen-8-ol; (1) (3aS, 4R, 9bR)-4- (4-Hydroxy-phenyl)-2,2-di oxo- 1 ,2,3,3a,4,9b-hexahydro-5-oxa-2k -thia- cyclopenta[a]naphthalen-8-ol; (m) (3aR, 4S, 9bS)-8-Hydroxy-4-(4-hydroxy-phenyl)- l,3a,4,9b-tetrahydro-3H-cyclopenta[c]chromen-2-one; (n) (3aS, 4R, 9bR)-8-Hydroxy-4-(4- hydroxy-phenyl)-l,3a,4,9b-tetrahydro-3H-cyclopenta[c]chromen-2-one; (o) (2S, 3aR, 4S, 9bS)-4-(4-Hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene-2,8-diol; (p) (2R, 3aS, 4R, 9bR)-4-(4-Hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro- cyclopenta[c]chromene-2,8-diol; (q) (3aR, 4S, 9bS)-2,2-Difluoro-4-(4-hydroxy-phenyl)- l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (r) (3aS, 4R, 9bR)-2,2-Difluoro-4-(4- hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (s) (2S, 3aR, 4S, 9bS)-4-(4-Hydroxy-phenyl)-2-trifluoromethyl-l,2,3,3a,4,9b-hexahydro- cyclopenta[c]chromen-8-ol; (t) (2R, 3aS, 4R, 9bR)-4-(4-Hydroxy-phenyl)-2- trifluoromethyl-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (u) (2R, 3aS, 4S, 9bS)-4-(4-Hydroxy-phenyl)-2-trifluoromethyl-l,2,3,3a,4,9b-hexahydro- cyclopenta[c]chromen-8-ol; (v) (2S, 3aS, 4R, 9bR)-4-(4-Hydroxy-phenyl)-2- trifluoromethyl-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (w) (2R, 3aR, 4S, 9bS)-2-Ethyl-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9bR-hexahydro-cyclopenta[c]chromene-2,8- diol; (x) (2S, 3aS, 4R, 9bR)-2-Ethyl-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9bR-hexahydro- cyclopenta[c]chromene-2,8-diol; (y) (2S, 3aS, 4R, 9bR)-2-Ethyl-4-(4-hydroxy-phenyl)- l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (z) (2S, 3aR, 4S, 9bS)-2-Ethyl-4-(4- hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (aa) (2S, 3aR, 4S, 9bS)-2-Ethyl-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (bb) (2R, 3aR, 4S, 9bS)-2-Ethyl-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro- cyclopenta[c]chromen-8-ol; (cc) (2S, 3aS, 4R, 9bR)-4-(4-Hydroxy-phenyl)-2-methoxy- l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (dd) (2R, 3aR, 4S, 9bS)-4-(4- Hydroxy-phenyl)-2-methoxy-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (ee) (2S, 3aS, 4R, 9bR)-Acetic acid 8-hydroxy-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro- cyclopenta[c]chromen-2-yl ester; (ff) (2R, 3aR, 4S, 9bS)-Acetic acid 8-hydroxy-4-(4- hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-2-yl ester; (gg) (2R, 3aS, 4R, 9bR)-2-Fluoro-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen- 8-ol; (hh) (2S, 3aR, 4S, 9bS)-2-Fluoro-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro- cyclopenta[c]chromen-8-ol; (ii) (2S, 3aS, 4R, 9bR)-2-Fluoro-4-(4-hydroxy-phenyl)- l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (jj) (2R, 3aR, 4S, 9bS)-2-Fluoro-4-(4- hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (kk) (2R, 3aR, 4S, 9bS)- and (2S, 3aS, 4R, 9bR)-8-Hydroxy-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro- cyclopenta[c]chromene-2-carbonitrile; (11) (2S, 3aR, 4S, 9bS)- and (2R, 3aS, 4R, 9bR)-8- Hydroxy-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromene-2- carbonitrile; (mm) (3aR, 4S, 9bS)- and (3aS, 4R, 9bR)-4-(4-Hydroxy-phenyl)-2-methylene- l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (nn) (3aR, 4S, 9bS)- and (3aS, 4R, 9bR)-2-Difluoromethylene-4-(4-hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro- cyclopenta[c]chromen-8-ol; (oo) (3aR, 4S, 9bS)- and (3aS, 4R, 9bR)-2-Ethynyl-4-(4- hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (pp) 2-Butyl-4-(4- hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (qq) 4-(4-Hydroxy- phenyl)-2-propyl-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (rr) 2-Ethyl-4-(4- hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; (ss) 2-Benzyl-4-(4- hydroxy-phenyl)-l,2,3,3a,4,9b-hexahydro-cyclopenta[c]chromen-8-ol; enantiomers thereof; or pharmaceutically acceptable salts thereof.
In some embodiments, the agonist can comprise a steroidal derivative. Examples of such agonists are described, for example, in International Publication No. WO 2019/035061 to Micalizio et ah, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be defined by Formula XXXIIA, XXXIIB, XXXIIC, or XXXTTD below
Figure imgf000053_0001
Formula XXXIIA
Figure imgf000054_0001
Formula XXXIID
wherein
each R2A and each R4A is independently absent or, when present, selected from the group consisting of hydrogen, Ci-io-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, halogen, hydroxy, -OR^, -SRAY, -S(0)2NRZ1RZ2, -S(0)2RZ1 , -S(0)RZ1 , -NRZ1RZ2, -
N(RZ1)C(0)RZ2, - N(RZ1)S(0)2RZ2, C6-io-aryl, and 5- to 10-membered heteroaryl, or two R2A together or two R4A together form an oxo,
wherein R^ is Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, -C(0)-Ci-io- alkyl, -C(0)-C6-io-aryl, -C(0)-heteroaryl, -C(0)-0-Ci-io-alkyl, -C(0)-0-C6-io-aryl, -C(O)- O-heteroaryl, -C(0)-NRZ1RZ2, -S(0)2RZ1 , C6-io-aryl, or 5- to 10-membered heteroaryl, wherein RAY is hydrogen, Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, - C(0)-Ci- 10-alkyl, -C(0)-C6-io-aryl, -C(0)-heteroaryl, C6-io-aryl, or 5- to 10-membered heteroaryl, wherein each of RZ 1 and RZ2 are independently hydrogen, Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, C6-io-aryl, 5- to 10-membered heteroaryl, hydroxy, or Ci-6- alkoxy;
each R3A is independently absent or, when present, selected from the group consisting of hydrogen, Ci-io-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, halogen, -O ^, -SRAY, - S(0)2NRZ1RZ2, -S(0)2Rz 1 , -S(0)RZ1 , -NRZ1RZ2, -N(RZ1)C(0)RZ2, -N(RZ1)S(0)2RZ2, Ce-io- aryl, and 5- to 10-membered heteroaryl;
R6A is selected from the group consisting of hydrogen, Ci-io-alkyl, C2-io-alkenyl, C2- 10- alkynyl, Ci-10-haloalkyl, halogen, oxygen, boronic acid, boronic acid ester, -ORBX, - SRby, - S(0)2NRZ1RZ2, -S(0)2Rz 1 , -S(0)RZ1 , -NRZ1RZ2, -N(RZ1)C(0)RZ2, - N(RZ1)S(0)2RZ2, C6-io-aryl, 5- to 10-membered heteroaryl, C6-io-aryl-Ci-6-alkyl, C6-io-aryl- C2-6-alkenyl, and C6-io-aryl-C2-6- alkynyl,
wherein RBX is Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, -C(0)-Ci-io- alkyl, -C(0)-C6-io-aryl, -C(0)-heteroaryl, C6-io-aryl, or 5- to 10-membered heteroaryl,
wherein RBY is hydrogen, Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-10-haloalkyl, - C(0)-Ci-io-alkyl, -C(0)-C6-io-aryl, -C(0)-heteroaryl, C6-io-aryl, or 5- to 10-membered heteroaryl;
RUA is selected from the group consisting of hydrogen, oxygen, and ORcx, wherein Rcx is Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, -C(0)-Ci-io- alkyl, -C(0)-C6-io-aryl, -C(0)-heteroaryl, C6-io-aryl, or 5- to 10-membered heteroaryl;
R13A is selected from the group consisting of Ci-6-alkyl and C6-io-aryl-Ci-6-alkyl, wherein the C6-io-aryl is optionally substituted one or more halogen, Ci-6-alkyl, C1-6- haloalkyl, or Ci-6- alkoxy;
each R16A is independently selected from the group consisting of hydrogen, hydroxy,
ORdx, -SRdy, -S(0)2NRZ1RZ2, -S(0)2Rz 1 , -S(0)RZ1 , -NRZ 1 RZ2, -N(RZ1)C(0)RZ2, - N(RZ1)S(0)2RZ2, and -C(0)-Ci-io-alkyl, or two R16A together form an oxo,
wherein RDX is Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, -C(0)-Ci-io- alkyl, -C(0)-C6-io-aryl, -C(0)-heteroaryl, C6-io-aryl, or 5- to 10-membered heteroaryl, wherein RDY is hydrogen, Ci-6-alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, -C(0)-Ci- 10-alkyl, -C(0)-C6-io-aryl, -C(0)-heteroaryl, C6-io-aryl, or 5- to 10-membered heteroaryl; each R17A is independently selected from the group consisting of hydrogen, Ci-io- alkyl, C2-io-alkenyl, C2-io-alkynyl, Ci-io-haloalkyl, and halogen, or two R17A together form an oxo;
each dotted line independently represents a single bond or a double bond;
the A ring is saturated, partially unsaturated, or completely unsaturated; and the B ring is saturated, partially unsaturated, or completely unsaturated;
wherein any C6-io-aryl or 5- to 10-membered heteroaryl is optionally substituted with one or more halogen, Ci-6-alkyl, Ci-6-haloalkyl, or Ci-6-alkoxy.
In certain embodiments, the agonist can be the compound defined below.
Figure imgf000056_0001
In some embodiments, the agonist can comprise a 4-cycloheptylphenol, such as the compound shown below.
Figure imgf000056_0002
In some embodiments, the agonist can comprise one of the compounds shown below.
Figure imgf000056_0003
In some embodiments, the agonist can comprise a polyhydroxyphthalazinone.
Examples of such agonists are described, for example, in International Publication No. WO 2018/214736 to Liang et ah, which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can be a compound defined by Formula XXXIII below
Figure imgf000057_0001
Formula XXXIII
wherein R1, R2, R3, and R4 are each independently hydrogen, hydroxy, C1-3 alkoxy or halogen;
R5 is hydrogen, C1-4 alkyl, C1-4 halogenated alkyl, phenyl or cyano; and
R6 is hydrogen or halogen.
In some embodiments, the halogen can be fluorine, chlorine or bromine.
In certain embodiments, R1, R2, and R3 are hydroxy, R4 and R6 are hydrogen; and R5 is hydrogen, C1-4 alkyl, C1-4 halogenated alkyl, phenyl or cyano.
In certain embodiments, R1, R2, and R3 are hydroxy, R4 and R6 are hydrogen; and R5 is chlorine or bromine.
In certain embodiments, R1, R2, and R3 are hydroxy; R4 is hydrogen or halogen; R5 is hydrogen; R6 is chlorine or bromine.
In some embodiments, the agonist can comprise the compound below.
Figure imgf000057_0002
Such agonists are described, for example, in International Publication No. WO 2017/010515 to Nakao et al., which is hereby incorporated by reference in its entirety.
In some embodiments, the agonist can comprise an isoflavone such as genistein, the structure of which is shown below.
Figure imgf000057_0003
In some examples, the agonist can comprise one of the compounds shown below.
Figure imgf000058_0001
Figure imgf000059_0001
Methods Treating Fibrotic Conditions
Non-Alcoholic Steatohepatitis (NASH) is increasingly recognized as the most prevalent chronic liver disease in the world and an important precedent condition to hepatocelullar carcinoma (J. Gastroenterol. (2018) 53:362-376). With effective hepatitis B and C treatment and vaccination programs, respectively, largely in place, NASH mediated HCC is expected to soon overtake all other known causes of HCC (Cell. Metab. 2019 Jan 8;29(1): 18-26). NASH prevalence is thought to approach 40% of obese adults, driving up overall incidence in lock step with a growing obesity epidemic, and represents one of the largest unmet medical needs in medicine. To date there exists no effective, FDA approved, therapy to address the pathological processes of liver steatosis, subsequent inflammation and resulting liver fibrosis associated with NASH progression. However, anti-NASH therapies remain an intense focus of the pharmaceutical industry (J Gastroenterol (2018) 53:362-376).
Like other liver pathologies, fatty liver disease displays marked sexual dimorphism such that rates of disease are higher in men than women, even when controlled for known risk factors (Adv Ther. 2017 Jun;34(6): 1291-1326.). This dimorphism suggests an important role for sex hormone signaling such that male hormones could be reasonably hypothesized to support NASH development, and conversely, female hormones expected to play a protective role. Several lines of evidence suggest that exogenous estrogen administration can mitigate fat accumulation and adverse metabolic changes associated with high fat diet (FASEB J. 2017 Jan;31(l):266-281.; Mol Cell Endocrinol. 2019 Jan 5;479:147-158.), ameliorate liver steatosis associated with a high-fat diet (Exp Biol Med (Maywood). 2017 Mar;242(6):606-616, Mol Med Rep. 2016 Jul;14(l):425-3 E), and prevent fibrosis associated with both high-fat diet (Exp Biol Med (Maywood). 2017 Mar;242(6):606-616) or other liver injury (World J Gastroenterol. 2002 Oct;8(5):883-7.; J Gastroenterol Hepatol. 2018 Mar;33(3):747-755 ). Together, these data highlight multiple potential beneficial mechanisms of action for therapeutic estrogen administration in NASH. However, administration of a pure, potent estrogen is not without limitations.
Therapeutic administration of steroidal endogenous estrogen preparations are associated with a number of limitations including but not limited to; exceedingly poor drug like properties, metabolic interconversion to other unwanted hormones, and unwanted severe estrogenic side-effects. For example, administration of a potent exogenous estrogen is accompanied with the fear of stimulating nascent breast cancer in a postmenopausal female NASH patient as was, with acknowledged controversy, shown to be a problem by the women’s health initiative (J Steroid Biochem Mol Biol. 2014 Jul; 142:4-11.). Likewise, in male patients, exogenous estrogen administration is associated with severe risk of deep- vein thrombosis, as was shown when DES was widely given as a prostate cancer therapeutic (Urology. 2001 Aug;58(2 Suppl 1): 108-13.).
The earliest descriptions selective estrogen receptor modulators (SERMS) revealed that desirable estrogen pharmacology could be separated from undesirable estrogen pharmacology (Curr Clin Pharmacol. 2013 May;8(2): 135-55.). Estrogen pharmacology was further advanced with the characterization of an additional, highly related, ERP isoform that displayed differential tissue distribution and biology as compared to ERa, the originally described receptor for endogenous estrogens (Proc Natl Acad Sci USA 93:5925-5930). As ERp biology became increasingly well characterized, it was accompanied with considerable interest in the development of therapeutic estrogens that selectively target ERp over ERa as well as other closely related nuclear hormone receptors (Expert Opin Ther Pat. 2010 Apr;20(4): 507-34.). One such ligand, Compound 1, is a carborane based highly ERP selective SERM.
Figure imgf000061_0001
Compound 1
It was hypothesized that Compound 1 could provide anti-NASH efficacy through combined anti-metabolic disease, antisteatotic, and anti-fibrotic effects. To test this hypothesis Compound 1 was administered once daily as two dose levels by oral gavage to male STAM model mice (Cell Metab. 2019 Jan 8;29(1): 18-26, slide #2). STAM mice are given pharmacologic beta-cell dysfunction to mimic Type 1 Diabetes and then given a 67% fat diet to recapitulate NASH progression. Mice treated during the steatosis phase for 7 weeks tolerated both dose levels very well. Both 10 and 100 mpk dose levels of Compound 1 were associated with prevention of plasma ALT and liver triglyceride levels associated with disease progression suggesting Compound 1 can prevent over hepatocyte necrosis and accumulation of hepatic lipids. Notably, this efficacy is on par with an FGF21 mimic currently under development by BMS. Critically, 100 mpk Compound 1 administration was also associated with significant reduction in liver fibrosis as measured by collagen staining (Sirius Red). The magnitude of this anti-fibrotic effects was similar to those reported in the same model for an FXR agonist in clinical development by Novartis (LJN452) and the BMS FGF21 mimic.
As this is the first demonstration of an ERP ligands' efficacy in the STAM model, these findings offer considerable promise for the combination of Compound 1 (or other carborane-based or non-carborane-based SERMS) with other anti-NASH approaches including but not limited to: SGLT inhibitors, PPARa/g/d agonists, ACC inhibitors, FXR ligands, FGF-19 and FGF-21 or mimics, GLP-1R agonists, LOXL-2 inhibitors, Galectin-3 inhibitors, HSP-47 inhibitors, ASK-1 inhibitors, VAP-1 inhibitors, SCD inhibitors, CCR2/5 antagonists and caspase inhibitors (J Gastroenterol (2018) 53:362-376).
Likewise, as this was the first demonstration of carborane-based SERMs’ anti- fibrotic effects these findings suggest that Compound 1 (or other carborane based or non- carborane-based SERMS) could be broadly useful in a number of fibrotic diseases including but not limited to; IPF, Calcineurin-induced renal fibrosis, Renal fibrosis NOS, Cardiac fibrosis associated with chronic heart failure (CHF), Fibrosis associated with Post-MI cardiac remodeling, Dupuytren's contracture, Fibrosis associated with RA, Liver fibrosis (viral, alcoholic, unknown origin), Peyronie's disease, Keloid or other scarring (post- surgical, etc.).
Example fibrotic conditions that can be treated or prevented using EίIb agonists include, but are not limited to, a fibrotic condition of the lung, liver, heart, vasculature, kidney, skin, gastrointestinal tract, bone marrow, or a combination thereof. Each of these conditions is described in more detail herein.
Fibrosis of the lung (also referred to herein as“pulmonary fibrosis”) is characterized by the formation of scar tissue within the lungs, which results in a decreased function. Pulmonary fibrosis is associated with shortness of breath, which progresses to discomfort in the chest weakness and fatigue, and ultimately to loss of appetite and rapid weight-loss. Approximately 500,000 people in the U.S. and 5 million worldwide suffer from pulmonary fibrosis, and 40,000 people in the Ei.S. die annually from the disease. Pulmonary fibrosis has a number of causes, including radiation therapy, but can also be due to smoking or hereditary factors (Meltzer, E B et al. (2008) Orphanet J. Rare Dis. 3:8).
Pulmonary fibrosis can occur as a secondary effect in disease processes such as asbestosis and silicosis, and is known to be more prevalent in certain occupations such as coal miner, ship workers and sand blasters where exposure to environmental pollutants is an occupational hazard (Green, F H et al. (2007) Toxicol Pathol. 35:f36-47). Other factors that contribute to pulmonary fibrosis include cigarette smoking, and autoimmune connective tissue disorders, like rheumatoid arthritis, scleroderma and systemic lupus erythematosus (SLE) (Leslie, K O et al. (2007) Semin Respir Crit. Care Med. 28:369-78; Swigris, J J et al. (2008) Chest. 133:271-80; and Antoniou, K M et al. (2008) Curr Opin Rheumatol. 20:686- 91). Other connective tissue disorders such as sarcoidosis can include pulmonary fibrosis as part of the disease (Paramothayan, S et al. (2008 ) Respir Med. 102: 1-9), and
infectious diseases of the lung can cause fibrosis as a long term consequence of infection, particularly chronic infections. Pulmonary fibrosis can also be a side effect of certain medical treatments, particularly radiation therapy to the chest and certain medicines like bleomycin, methotrexate, amiodarone, busulfan, and nitrofurantoin (Catane, R et al.
(1979) Int J Radiat Oncol Biol Rhys. 5: 1513-8; Zisman, D A et al. (2001) Sarcoidosis Vase Diffuse Lung Dis. 18:243-52; Rakita, L et al. (1983) Am Heart J. 106:906-16; Twohig, K J et al. (1990) Clin Chest Med. 11:31-54; and Witten C M. ( 1989) Arch Rhys Med.
Rehabil. 70:55-7). In other embodiments, idiopathic pulmonary fibrosis can occur where no clear causal agent or disease can be identified. Increasingly, it appears that genetic factors can play a significant role in these cases of pulmonary fibrosis (Steele, M P et al. (2007) Respiration 74:601-8; Brass, D M et al. (2007) ProcAm Thorac Soc. 4:92-100 and du Bois R M. (2006) Semin Respir Crit. Care Med. 27:581-8).
In some examples, the fibrotic condition of the lung can be chosen from one or more of: pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), or bronchiectasis.
In other examples, the pulmonary fibrosis can include, but is not limited to, pulmonary fibrosis associated with chronic obstructive pulmonary disease (COPD), scleroderma, pleural fibrosis, chronic asthma, acute lung syndrome, amyloidosis, bronchopulmonary dysplasia, Caplan's disease, Dressler's syndrome, histiocytosis X, idiopathic pulmonary haemosiderosis, lymphangiomyomatosis, mitral valve stenosis, polymyositis, pulmonary edema, pulmonary hypertension (e.g., idiopathic pulmonary hypertension (IPH)), pneumoconiosis, radiotherapy (e.g., radiation induced fibrosis), rheumatoid disease, Shaver's disease, systemic lupus erythematosus, systemic sclerosis, tropical pulmonary eosinophilia, tuberous sclerosis, Weber-Christian disease, Wegener's granulomatosis, Whipple's disease, or exposure to toxins or irritants (e.g., pharmaceutical drugs such as amiodarone, bleomycin, busulphan, carmustine, chloramphenicol,
hexamethonium, methotrexate, methysergide, mitomycin C, nitrofurantoin, penicillamine, peplomycin, and practolol; inhalation of talc or dust, e.g., coal dust, silica). In certain embodiments, the pulmonary fibrosis is associated with an inflammatory disorder of the lung, e.g., asthma, COPD.
In some embodiments, the fibrotic condition can be a fibrotic condition of the liver (also referred to herein as“hepatic fibrosis”), such as fatty liver disease e.g., steatosis such as nonalcoholic steatohepatitis (NASH), biliary fibrosis, cholestatic liver disease (e.g., primary biliary cirrhosis (PBC), and cholangiopathies (e.g., chronic cholangiopathies)).
In certain embodiments, the fibrotic of the liver or hepatic fibrosis can be chosen from one or more of: fatty liver disease, steatosis (e.g., nonalcoholic steatohepatitis
(NASH), cholestatic liver disease, primary biliary cirrhosis (PBC), biliary fibrosis, cirrhosis, alcohol induced liver fibrosis, biliary duct injury, infection or viral induced liver fibrosis, congenital hepatic fibrosis, autoimmune hepatitis, or cholangiopathies (e.g., chronic cholangiopathies).
In certain embodiments, hepatic or liver fibrosis includes, but is not limited to, hepatic fibrosis associated with alcoholism, viral infection, e.g., hepatitis (e.g., hepatitis C, B or D), autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), progressive massive fibrosis, exposure to toxins or irritants (e.g., alcohol, pharmaceutical drugs and environmental toxins such as arsenic), alpha-1 antitrypsin deficiency, hemochromatosis, Wilson's disease, galactosemia, or glycogen storage disease. In certain embodiments, the hepatic fibrosis is associated with an inflammatory disorder of the liver.
In some embodiments, the fibrotic condition can be a fibrotic condition of the heart or vasculature, such as myocardial fibrosis. Fibrotic conditions of the heart or vasculature can include, but are not limited to, myocardial fibrosis (e.g., myocardial fibrosis associated with radiation myocarditis, a surgical procedure complication (e.g., myocardial post operative fibrosis), vascular restenosis, atherosclerosis, cerebral disease, peripheral vascular disease, infectious diseases (e.g., Chagas disease, bacterial, trichinosis or fungal
myocarditis)); granulomatous, metabolic storage disorders (e.g., cardiomyopathy, hemochromatosis); developmental disorders (e.g., endocardial fibroelastosis);
arteriosclerotic, or exposure to toxins or irritants (e.g., drug induced cardiomyopathy, drug induced cardiotoxicity, alcoholic cardiomyopathy, cobalt poisoning or exposure). In certain embodiments, the myocardial fibrosis is associated with an inflammatory disorder of cardiac tissue (e.g., myocardial sarcoidosis).
In some embodiments, the fibrotic condition can be a fibrotic condition of the kidney, such as renal fibrosis (e.g., chronic kidney fibrosis). Renal fibrosis can include, but is not limited to, nephropathies associated with injury/fibrosis (e.g., chronic nephropathies associated with diabetes (e.g., diabetic nephropathy)), lupus, scleroderma of the kidney, glomerular nephritis, focal segmental glomerular sclerosis, IgA nephropathyrenal fibrosis associated with human chronic kidney disease (CKD), chronic kidney fibrosis, nephrogenic systemic fibrosis, chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction (e.g., fetal partial urethral obstruction), chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis (e.g., focal segmental glomerulosclerosis (FSGS)), progressive glomerulonephrosis (PGN),
endothelial/thrombotic microangiopathy injury, scleroderma of the kidney, HIV-associated nephropathy (HIVVAN), or exposure to toxins, irritants, chemotherapeutic agents. In one embodiment, the kidney fibrosis is mediated by a bone morphogeneic protein (BMP). In certain embodiments, the renal fibrosis is a result of an inflammatory disorder of the kidney.
In some embodiments, the fibrotic condition can be a fibrotic condition of the bone marrow. In certain embodiments, the fibrotic condition of the bone marrow is myelofibrosis (e.g., primary myelofibrosis (PMF)), myeloid metaplasia, chronic idiopathic myelofibrosis, or primary myelofibrosis. In other embodiments, bone marrow fibrosis is associated with a hematologic disorder chosen from one or more of hairy cell leukemia, lymphoma, or multiple myeloma.
In other embodiments, the bone marrow fibrosis can be associated with one or more myeloproliferative neoplasms (MPN) chosen from: essential thrombocythemia (ET), polycythemia vera (PV), mastocytosis, chronic eosinophilic leukemia, chronic neutrophilic leukemia, or other MPN.
In some examples, the fibrotic condition can be primary myelofibrosis. Primary myelofibrosis (PMF) (also referred to in the literature as idiopathic myeloid metaplasia, and Agnogenic myeloid metaplasia) is a clonal disorder of multipotent hematopoietic progenitor cells (reviewed in Abdel-Wahab, O. et al. (2009) Annu. Rev. Med. 60:233-45; Varicchio, L. et al. (2009) Expert Rev. Hematol. 2(3):315-334; Agrawal, M. et al. (2010) Cancer 1-15). The disease is characterized by anemia, splenomegaly and extramedullary hematopoiesis, and is marked by progressive marrow fibrosis and atypical megakaryocytic hyperplasia. CD34+ stem/progenitor cells abnormally traffic in the peripheral blood and multi organ extramedullary erythropoiesis is a hallmark of the disease, especially in the spleen and liver. The bone marrow structure is altered due to progressive fibrosis, neoangiogenesis, and increased bone deposits. A significant percentage of patients with PMF have gain-of- function mutations in genes that regulate hematopoiesis, including Janus kinase 2 (JAK2) (~50%) (e.g., JAK2V617F) or the thrombopoietin receptor (MPL) (5-10%), resulting in abnormal megakaryocyte growth and differentiation. Studies have suggested that the clonal hematopoietic disorder leads to secondary proliferation of fibroblasts and excessive collagen deposition. Decreased bone marrow fibrosis can improve clinical signs and symptoms, including anemia, abnormal leukocyte counts, and splenomegaly.
Bone marrow fibrosis can be observed in several other hematologic disorders including, but not limited to hairy cell leukemia, lymphoma, and multiple myeloma.
However, each of these conditions is characterized by a constellation of clinical, pathologic, and molecular findings not characteristic of PMF (see Abdel-Wahab, O. et al. (2009) supra at page 235).
In other embodiments, the bone marrow fibrosis can be secondary to non- hematologic disorders, including but not limited to, solid tumor metastases to bone marrow, autoimmune disorders (systemic lupus erythematosus, scleroderma, mixed connective tissue disorder, polymyositis), and secondary hyperparathyroidism associated with vitamin D deficiency (see Abdel-Wahab, O. et al. (2009) supra at page 235). In most cases, it is possible to distinguish between these disorders and PMF, although in rare cases the presence of the JAK2V617F or MPLW515L/K mutation can be used to demonstrate the presence of a clonal MPN and to exclude the possibility of reactive fibrosis.
Optionally, monitoring a clinical improvement in a subject with bone marrow fibrosis can be evaluated by one or more of: monitoring peripheral blood counts (e.g., red blood cells, white blood cells, platelets), wherein an increase in peripheral blood counts is indicative of an improved outcome. In other embodiments, clinical improvement in a subject with bone marrow fibrosis can be evaluated by monitoring one or more of: spleen size, liver size, and size of extramedullary hematopoiesis, wherein a decrease in one or more of these parameters is indicative of an improved outcome.
In other embodiments, the fibrotic condition can be a fibrotic condition of the skin. In certain embodiments, the fibrotic condition is chosen from one or more of: skin fibrosis and/or scarring, post-surgical adhesions, scleroderma (e.g., systemic scleroderma), or skin lesions such as keloids.
In certain embodiments, the fibrotic condition can be a fibrotic condition of the gastrointestinal tract. Such fibrotic conditions can be associated with an inflammatory disorder of the gastrointestinal tract, e.g., fibrosis associated with scleroderma; radiation induced gut fibrosis; fibrosis associated with a foregut inflammatory disorder such as Barrett's esophagus and chronic gastritis, and/or fibrosis associated with a hindgut inflammatory disorder, such as inflammatory bowel disease (IBD), ulcerative colitis and Crohn's disease. In certain embodiments, the fibrotic condition can be diffuse scleroderma.
Fibrotic conditions can further include diseases that have as a manifestation fibrotic disease of the penis, including Peyronie's disease (fibrosis of the cavernous sheaths leading to contracture of the investing fascia of the corpora, resulting in a deviated and painful erection).
In some cases, the fibrotic condition can comprise Dupuytren’s contracture (palmar fibromatosis).
In some cases, the fibrotic condition can comprise fibrosis associated with rheumatoid arthritis. In certain embodiments, the fibrotic condition can be selected from pulmonary fibrosis, bronchiectasis, interstitial lung disease; fatty liver disease; cholestatic liver disease, biliary fibrosis, hepatic fibrosis; myocardial fibrosis; and renal fibrosis.
In certain embodiments, the fibrotic condition can be selected from biliary fibrosis, hepatic fibrosis, pulmonary fibrosis, myocardial fibrosis and renal fibrosis
In certain embodiments, the fibrotic condition can be selected from nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
Other fibrotic conditions that can be treated with the methods and compositions of the invention include cystic fibrosis, endomyocardial fibrosis, mediastinal fibrosis, sarcoidosis, scleroderma, spinal cord injury/fibrosis.
A number of models in which fibrosis is induced are available in the art.
Administration of ERp agonists can be readily used to evaluate whether fibrosis is ameliorated in such models. Examples of such models, include but are not limited to, the unilateral ureteral obstruction model of renal fibrosis (see Chevalier et al.,“Ureteral Obstruction as a Model of Renal Interstitial Fibrosis and Obstructive Nephropathy” Kidney International (2009) 75: 1145-1152), the bleomycin induced model of pulmonary fibrosis (see Moore and Hogaboam“Murine Models of Pulmonary Fibrosis” Am. J Physiol. Lung. Cell. Mol. Physiol. (2008) 294:L152-L160), a variety of liver/biliary fibrosis models (see Chuang et al.,“Animal Models of Primary Biliary Cirrhosis” Clin Liver Dis (2008) 12:333- 347; Omenetti, A. et al. (2007) Laboratory Investigation 87:499-514 (biliary duct-ligated model); or a number of myelofibrosis mouse models as described in Varicchio, L. (2009) supra. Regardless of the model, ERp agonists can be evaluated in essentially three paradigms: 1) test whether ERp agonists can inhibit the fibrotic state; 2) test whether ERp agonists can stop fibrotic progression once initiated; and/or 3) test whether ERP agonists can reverse the fibrotic state once initiated.
In certain embodiments, the fibrotic condition is provided in a tissue (e.g., biliary tissue, liver tissue, lung tissue, heart tissue, kidney tissue, skin tissue, gut tissue, or neural tissue). In certain embodiments, the tissue is biliary tissue. In certain embodiments, the tissue is liver tissue. In certain embodiments the tissue is lung tissue. In certain
embodiments, the tissue is heart tissue. In certain embodiments, the tissue is kidney tissue. In certain embodiments, the tissue is skin tissue. In certain embodiments, the tissue is gut tissue. In certain embodiments, the tissue is bone marrow tissue. In certain embodiments, the tissue is epithelial tissue. In certain embodiments, the tissue is neural tissue. Also provided are composition for use, and use of, an ERp agonist, alone or in combination with another agent, for preparation of one or more medicaments for use in reducing fibrosis, or treatment of a fibrotic condition.
Pharmaceutical Compositions, Dosage and Administration
In some embodiments, the above-described methods can comprise providing an ERp agonist in a pharmaceutical composition.
Pharmaceutical compositions can be formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (e.g., aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), capsules, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection such as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; intravaginally or intrarectally, for example, as a pessary, cream or foam; sublingually; ocularly;
transdermally; pulmonarily; or nasally.
Pharmaceutically acceptable excipients include any and all fillers, binders, surfactants, disintegrants, sugars, polymers, antioxidants, solubilizing or suspending agents, chelating agents, preservatives, buffering agents and/or lubricating agents, or combinations thereof, as suited to the particular dosage form desired and according to the judgment of the formulator. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various pharmaceutically acceptable excipients used in preparing compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any component of the composition, its use is contemplated to be within the scope of this invention. In general, the compositions are prepared by uniformly and intimately bringing into association the agonist with one or more excipients and then, if necessary, shaping the product.
When the agonist is administered to humans or animals it can be given per se or as a pharmaceutical composition containing, for example, about 0.1 to 99%, or about 10 to 50%, or about 10 to 40%, or about 10 to 30%, or about 10 to 20%, or about 10 to 15% of the agonist in combination with a pharmaceutically acceptable excipient. Actual dosage levels of the agonist in the pharmaceutical compositions can be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular subject, composition, and mode of administration, without being toxic to the subject.
The selected dosage level will depend upon a variety of factors including, for example, the activity of the particular agonist employed, the route of administration, the time of administration, the rate of excretion or metabolism, the rate and extent of absorption, the duration of the treatment, other drugs, compounds or materials used in combination with the agonist, the age, sex, weight, condition, general health and prior medical history of the subject, and other similar factors well known in the medical arts.
In general, a suitable daily dose of an agonist will be that amount which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, oral, intravenous and subcutaneous doses of the agonist for a subject, when used for the indicated effects, will range from about 0.0001 mg to about 100 mg per day, or about 0.001 mg to about 100 mg per day, or about 0.01 mg to about 100 mg per day, or about 0.1 mg to about 100 mg per day, or about 0.0001 mg to about 500 mg per day, or about 0.001 mg to about 500 mg per day, or about 0.01 mg to about 500 mg per day, or about 0.1 mg to about 500 mg per day.
The subject receiving the treatment can be any animal in need, including primates (e.g. humans), equines, cattle, swine, sheep, poultry, dogs, cats, mice and rats.
The agonist can be administered daily, every other day, three times a week, twice a week, weekly, or bi-weekly. The dosing schedule can include a“drug holiday,” i.e., the drug can be administered for two weeks on, one week off, or three weeks on, one week off, or four weeks on, one week off, etc., or continuously, without a drug holiday. The agonist can be administered orally, intravenously, intraperitoneally, topically, transdermally,
intramuscularly, subcutaneously, intranasally, sublingually, or by any other route.
Combination Therapies
The ERP agonists can be administered in combination with one or more therapeutic agents. Exemplary therapeutic agents include, but are not limited to, anti-fibrotics, corticosteroids, anti-inflammatories, immunosuppressants, chemotherapeutic agents, anti metabolites, and immunomodulators.
By“in combination with,” it is not intended to imply that the therapeutic agent and the agonist must be administered at the same time and/or formulated for delivery together, although these methods of delivery are possible. The agonist can be administered concurrently with, prior to, or subsequent to, one or more other additional agents. In general, each therapeutic agent will be administered at a dose and/or on a time schedule determined for that particular agent. In will further be appreciated that the therapeutic agent utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of the agonist with the agent and/or the desired therapeutic effect to be achieved.
In general, it is expected that additional therapeutic agents employed in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. The determination of the mode of administration and the correct dosage for each agent or combination therapy is well within the knowledge of the skilled clinician.
In some embodiments, the agonist is a first line treatment for the fibrotic condition, i.e., it is used in a subject who has not been previously administered another drug intended to treat the condition.
In other embodiments, the agonist is a second line treatment for
the fibrotic condition, i.e., it is used in a subject who has been previously administered another drug intended to treat the condition.
In other embodiments, the agonist is a third or fourth line treatment for
the fibrotic condition, i.e., it is used in a subject who has been previously administered two or three other drugs intended to treat the condition.
In some embodiments, the agonist is administered to a subject following a surgical procedure, such as a surgical excision/removal of tissue.
In some embodiments, a agonist is administered to a subject before, during, and/or after radiation treatment.
In embodiments where two agents are administered, the two agents can be administered concurrently (i.e., essentially at the same time, or within the same treatment) or sequentially (i.e., one immediately following the other, or alternatively, with a gap in between administration of the two). In some embodiments, the agonist is administered sequentially (i.e., after the first therapeutic).
In embodiments where a fibrotic condition of the bone marrow is treated, the agonist can be administered in combination with an agent chosen from a Jak2 inhibitor (including, but not limited to, INCB018424, XL019, TG101348, or TG101209), an immunomodulator, e.g., an IMID (including, but not limited to thalidomide, lenalidomide, or panolinomide), hydroxyurea, an androgen, erythropoietic stimulating agents, prednisone, danazol, HD AC inhibitors, or other agents or therapeutic modalities (e.g., stem cell transplants, or radiation).
An example of suitable therapeutics for use in combination with the agonist for treatment of heart fibrosis includes, but is not limited to, eplerenone, furosemide, pycnogenol, spironolactone, TcNC 100692, torasemide (e.g., prolonged release form of torasemide), and combinations thereof.
An example of suitable therapeutics for use in combination with the agonist for treatment of kidney fibrosis includes, but is not limited to, cyclosporine, cyclosporine A, daclizumab, everolimus, gadofoveset trisodium (ABLAVAR®), imatinib mesylate
(GLEEVEC®), matinib mesylate, methotrexate, mycophenolate mofetil, prednisone, sirolimus, spironolactone, STX-100, tamoxifen, TheraCLEC™, and combinations thereof.
An example of suitable therapeutics for use in combination with the agonist for treatment of skin fibrosis includes, but is not limited to, Bosentan (Tracleer), pl44, pentoxifylline; pirfenidone; pravastatin, STI571, Vitamin E, and combinations thereof.
An example of suitable therapeutics for use in combination with the agonist for treatment of gastrointestinal fibrosis includes, but is not limited to, ALTEi-135, bucelipase alfa (INN), DCI1020, EUR-1008 (ZENPEP™), ibuprofen, Lym-X-Sorb powder, pancrease MT, pancrelipase (e.g., pancrelipase delayed release), pentade canoic acid (PA), repaglinide, TheraCLEC™, triheptadecanoin (THA), ULTRASE MT20, ursodiol, and combinations thereof.
An example of suitable therapeutics for use in combination with the agonist for treatment of lung fibrosis includes, but is not limited to, 18-FDG, AB0024, ACT-064992 (macitentan), aerosol interferon-gamma, aerosolized human plasma-derived alpha- 1 antitrypsin, alpha 1 -proteinase inhibitor, ambrisentan, amikacin, amiloride, amitriptyline, anti-pseudomonas IgY gargle, ARIKACE™, AUREXIS® (tefibazumab), AZAPRED, azathioprine, azithromycin, azithromycin, AZLI, aztreonam lysine, BIBF1120, Bio-25 probiotic, bosentan, Bramitob®, calfactant aerosol, captopril, CC-930, ceftazidime, ceftazidime, cholecalciferol (Vitamin D3), ciprofloxacin (CIPRO®, BAYQ3939), CNTO 888, colistin CF, combined Plasma Exchange (PEX), rituximab, and corticosteroids, cyclophosphamide, dapsone, dasatinib, denufosol tetrasodium (INS37217), dornase alfa (PULMOZYME®), EPI-hNE4, erythromycin, etanercept, FG-3019, fluticasone, FTI, GC1008, GS-9411, hypertonic saline, ibuprofen, iloprost inhalation, imatinib mesylate (GLEEVEC®), inhaled sodium bicarbonate, inhaled sodium pyruvate, interferon gamma- lb, interferon-alpha lozenges, isotonic saline, IW001, KB001, losartan, lucinactant, mannitol, meropenem, meropenem infusion, miglustat, minocycline, Molil901, MP-376 (levofloxacin solution for inhalation), mucoid exopolysaccharide P. aeruginosa immune globulin IV, mycophenolate mofetil, n-acetylcysteine, N-acetylcysteine (NAC), NaCl 6%, nitric oxide for inhalation, obramycin, octreotide, oligoG CF-5/20, Omalizumab, pioglitazone, piperacillin-tazobactam, pirfenidone, pomalidomide (CC-4047), prednisone, prevastatin, PRM-151, QAX576, rhDNAse, SB656933, SB-656933-AAA, sildenafil, tamoxifen, technetium [Tc-99 m] sulfur colloid and Indium [In-111] DTPA,
tetrathiomolybdate, thalidomide, ticarcillin-clavulanate, tiotropium bromide, tiotropium RESPIMAT® inhaler, tobramycin (GERNEBCIN®), treprostinil, uridine, valganciclovir (VALCYTE®), vardenafil, vitamin D3, xylitol, zileuton, and combinations thereof.
An example of suitable therapeutics for use in combination with the agonist for treatment of liver fibrosis includes, but is not limited to, adefovir dipivoxil, candesartan, colchicine, combined ATG, mycophenolate mofetil, and tacrolimus, combined cyclosporine microemulsion and tacrolimus, elastometry, everolimus, FG-3019, Fuzheng Huayu, GI262570, glycyrrhizin (monoammonium glycyrrhizinate, glycine, L-cysteine
monohydrochloride), interferon gamma-lb, irbesartan, losartan, oltipraz, ORAL IMPACT®, peginterferon alfa-2a, combined peginterferon alfa-2a and ribavirin, peginterferon alfa-2b (SCH 54031), combined peginterferon alpha-2b and ribavirin, praziquantel, prazosin, raltegravir, ribavirin (REBETOL®, SCH 18908), ritonavir-boosted protease inhibitor, pentoxyphilline, tacrolimus, tauroursodeoxycholic acid, tocopherol, ursodiol, warfarin, and combinations thereof.
An example of other suitable therapeutics for use in combination with the agonist for treatment of cystic fibrosis includes, but is not limited to, 552-02, 5- methyltetrahydrofolate and vitamin B 12, Ad5-CB-CFTR, Adeno-associated virus-CFTR vector, albuterol, alendronate, alpha tocopherol plus ascorbic acid, amiloride HC1, aquADEK™, ataluren (PTC 124), AZD1236, AZD9668, azithromycin, bevacizumab, biaxin (clarithromycin), BIIL 283 BS (amelubent), buprofen, calcium carbonate, ceftazidime, cholecalciferol, choline supplementation, CPX, cystic fibrosis transmembrane conductance regulator, DHA-rich supplement, digitoxin, cocosahexaenoic acid (DHA), doxycycline, ECGC, ecombinant human IGF-1, educed glutathione sodium salt, ergocalciferol (vitamin D2), fluorometholone, gadobutrol (GADOVIST®, BAY86-4875), gentamicin, ghrelin, glargine, glutamine, growth hormone, GS-9411, H5.001CBCFTR, human recombinant growth hormone, hydroxychloroquine, hyperbaric oxygen, hypertonic saline, IH636 grape seed proanthocyanidin extract, insulin, interferon gamma- lb, IoGen (molecular iodine), iosartan potassium, isotonic saline, itraconazole, IV gallium nitrate (GANITE®) infusion, ketorolac acetate, lansoprazole, L-arginine, linezolid, lubiprostone, meropenem, miglustat, MP-376 (levofloxacin solution for inhalation), normal saline IV, Nutropin AQ, omega-3 triglycerides, pGM169/GL67A, pGT-1 gene lipid complex, pioglitazone, PTC 124,
QAU145, salmeterol, SB656933, SB656933, simvastatin, sitagliptin, sodium 4- phenylbutyrate, standardized turmeric root extract, tgAAVCF, TNF blocker, TOBI, tobramycin, tocotrienol, unconjugated Isoflavones 100, vitamin: choline bitartrate (2- hydroxy ethyl) trimethylammonium salt 1 : 1, VX-770, VX-809, Zinc acetate, and combinations thereof.
A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims.
EXAMPLES
Compound l is a selective estrogen receptor beta (ERP) agonist. The in vivo efficacy of compound 1 (shown below) was evaluated in a STAM model of non-alcoholic steatohepatitis (NASH, a fibrotic condition).
Figure imgf000073_0001
Compound 1
Materials and Methods
Compound 1 was prepared using methods described previously. To prepare dosing solutions, compound 1 was weighed and suspended in vehicle (5% DMSO, 5% Tween® 20, water). Compound 1 was administered orally in a volume of lOmL/kg. Compound 1 was administered at two dose levels of 10 and 100 mg/kg once daily.
Pathogen-free 14 day-pregnant C57BU6 mice were obtained for use in this study. All animals used in this study were housed and cared for in accordance with industry standards. NASH was established in mule mice by a single subcutaneous injection of 200 pg streptozotocin (STZ, Sigma Aldrich, USA) two days after birth and feeding with a high fat diet (HFD, 57 kcal% fat, Cat# HFD32, CLEA Japan Inc., Japan) ad libitum after 4 weeks of age (day 28). NASH mice were randomized into three groups of eight mice at five weeks of age (day 35 ± 2) the day before the start of treatment based on their body weight. Littermate control mice without STZ priming (n=8) were set up for control purposes.
Individual body weight was measured daily during the treatment period. Survival, clinical signs, and behavior of the mice was also monitored daily.
Measurement of Plasma Biochemistry . To evaluate plasma biochemistry, non- fasting blood was collected in polypropylene tubes with anticoagulant (Novo-Heparin, Mochida Pharmaceutical Co. Ltd., Japan) and centrifuged at 1 ,000 xg for 1 5 minutes at 4°C. The supernatant was collected and stored at -8Q°C until use. Plasma ALT levels were measured by FUJI DRJ-CHEM 7000 (Fujifilm, Japan)
Measurement of liver biochemistry. Liver total lipid-extracts were obtained by Folch's method (Folch J. et al, J. Biol. Chem. 1957;226: 497). Liver samples were homogenized in chloroform-methanol (2: 1, v/v) and incubated overnight at room
temperature. After washing with chloroform-methanol-water (8:4:3, v/v/v), the extracts were evaporated to dryness, and dissolved in isopropanol. Liver triglyceride contents were measured by Triglyceride E-test (Wako Pure Chemical Industries, Ltd., Japan).
Histological Analysis. For HE staining, sections were cut from paraffin blocks of liver tissue prefixed in Bouin's solution and stained with Lillie-Mayer's Hematoxylin (Muto Pure Chemicals Co., Ltd., Japan) and eosin solution (Wako Pure Chemical Industries). NAFLD Activity score (NAS) was calculated according to the criteria of Kleiner (Kleiner DE. et al, Hepatology, 2005;41 : 1313). To visualize collagen deposition, Bouin's fixed liver sections were stained using picro-Sirius red solution (Waldeck, Germany). For quantitative analysis of fibrosis area, bright field images of Sirius red-stained sections were captured around the central vein using a digital camera (DFC295; Leica, Germany) at 200-fold magnification, and the positive areas in 5 fields/section were measured using ImageJ software (National Institute of Health, USA).
Sample collection. For plasma samples, non-fasting blood was collected in polypropylene tubes with anticoagulant (Novo-Heparin) and centrifuged at 1,000 xg for 15 minutes at 4°C. The supernatant was collected and stored at -80°C for biochemistry (20 pL) and shipping (remaining). For liver samples, left lateral lobe was collected and cut into six pieces. Two pieces of left lateral lobe, left and right medial lobes, and caudate lobe were snap frozen in liquid nitrogen and stored at -80°C for shipping. The other two pieces of left lateral lobe were fixed in Bouin's solution and then embedded in paraffin. Paraffin blocks were stored at room temperature for histology. The remaining pieces of left lateral lobe were embedded in O.C.T. compound and quick frozen in liquid nitrogen. O.C.T. blocks were stored at -80°C. The right lobe was snap frozen in liquid nitrogen and stored at -80°C for liver biochemistry.
Statistical tests. Statistical analyses were performed using Bonferroni Multiple Comparison Test on GraphPad Prism 6 (GraphPad Software Inc., USA). P values <0.05 were considered statistically significant. A trend or tendency was assumed when a one- tailed t-test returned P values <0.1. Results were expressed as mean ± SD.
Experimental Design and Treatment
Study Groups. The populations of mice were divided into four study groups:
Group 1 : Normal. Eight normal mice were kept without any treatment until sacrifice. Group 2: Vehicle. Eight NASH mice were orally administered vehicle (5%
DMSO, 5% Tween® 20, water) in a volume of 10 mL/kg once daily from 5 to 12 weeks of age.
Group 3: Compound High. Eight NASH mice were orally administered vehicle supplemented with compound 1 at a dose of 100 mL/kg once daily from 5 to 12 weeks of age.
Group 4: Compound Low. Eight NASH mice were orally administered vehicle supplemented with compound 1 at a dose of 10 mL/kg once daily from 5 to 12 weeks of age.
The table below summarizes the treatment schedule.
Figure imgf000075_0001
Animal Monitoring and Sacrifice. The viability, clinical signs and behavior were monitored daily. Body weight was recorded before the treatment. Mice were observed for significant clinical signs of toxicity, moribundity and mortality approximately 60 minutes after each administration. The animals were sacrificed at 12 weeks of age by exsanguination through direct cardiac puncture under isoflurane anesthesia (Pfizer Inc.).
Results
Body weight changes and general condition. Figure 1 illustrates the average body weight change observed in the four study groups over the course of the treatment period. Mean body weight in all groups gradually increased during the treatment period. Mean body weights of the Vehicle group were significantly lower than that of the Normal group from Day 0 to Day 49. There were no significant differences in mean body weights at any day during the treatment period between the Vehicle group and the Compound treatment groups.
During the treatment period, mice found dead before reaching Day 49 were as follows; three out of 8 mice were found dead in the Vehicle group. Two out of 8 mice were found dead in the Compound high and Compound low groups.
Body weight on the day of sacrifice and liver weight. Figure 2A is a plot showing the body weight of animals on the day of sacrifice. The Vehicle group showed a significant decrease in mean body weight on the day of sacrifice compared with the Normal group. There were no significant differences in mean body weight on the day of sacrifice between the Vehicle group and the Compound treatment groups.
Figure 2B is a plot showing the liver weight of animals on the day of sacrifice. The Vehicle group showed a significant increase in mean liver weight compared with the Normal group. There were no significant differences in mean liver weight between the Vehicle group and the Compound treatment groups
Figure 2C is a plot showing the liver-to-body weight ratio of animals on the day of sacrifice. The Vehicle group showed a significant increase in mean liver-to-body weight ratio compared with the Normal group. Mean liver-to-body weight ratio in the Compound high group tended to increase compared with the Vehicle group. There was no significant difference in mean liver-to-body weight ratio between the Vehicle group and the Compound low group The results of these studies are summarized in the table below.
Figure imgf000077_0001
Biochemistry. Figure 3 A is a plot showing the plasma alanine aminotransferase (ALT) levels on the day of sacrifice. The Vehicle group showed a significant increase in plasma ALT level compared with the Normal group. The Compound high and low groups showed significant decreases in plasma ALT levels compared with the Vehicle group
Figure 3B is a plot showing liver triglyceride levels (in mg/g liver) on the day of sacrifice. The Vehicle group showed a significant increase in liver triglyceride content compared with the Normal group. The Compound high and low groups showed significant decreases in liver triglyceride compared with the Vehicle group.
The results of these studies are summarized in the table below.
Figure imgf000077_0002
Histological analyses. Liver sections were HE-stained and imaged as described above. Steatosis, lobular inflammation, and hepatocyte ballooning was evaluated to calculate a NAFLD Activity Score. The definition of NAS components is included in the table below.
Figure imgf000078_0001
Liver sections from the Vehicle group exhibited micro- and macrovesicular fat deposition, hepatocellular ballooning and inflammatory cell infiltration compared with the Normal group. The Vehicle group showed a significant increase in NAS compared with the Normal group. NAS in the Compound high and low groups tended to decrease compared with the Vehicle group.
Figure 4 is a plot showing the non-alcoholic fatty liver disease (NAFLD) activity score on the day of sacrifice. Figure 5A is a plot showing the steatosis score on the day of sacrifice. Figure 5B is a plot showing the inflammation score on the day of sacrifice. Figure 5C is a plot showing the ballooning score on the day of sacrifice. The results of these studies are summarized in the table below.
Figure imgf000078_0002
Sirius red staining and the fibrosis area. Liver sections were stained with Sirius Red an imaged, and the positive area was determined as described above. Liver sections from the Vehicle group showed increased collagen deposition in the pericentral region of liver lobule compared with the Normal group. The Vehicle group showed a significant increase in the fibrosis area (Sirius red-positive area) compared with the Normal group. The
Compound high group showed a significant decrease in the fibrosis area compared with the Vehicle group.
Figure 6 is a plot showing the fibrosis area (sirius red-positive area, %) on the day of sacrifice. The results of these studies are summarized in the table below.
Figure imgf000079_0001
Summary and Conclusion
Treatment with compound 1 (a selective ER)3 agonist) showed significant reduction in plasma ALT levels and liver triglycelide content compared with Vehicle group.
Treatment with compound 1 showed a decreasing trend in NAFLD Activity Score (NAS) compared with Vehicle group. Treatment with compound 1 of high dose showed significant reduction in the fibrosis area compared with Vehicle group, in a dose dependent manner.
In conclusion, the compound 1 showed hepatoprotective potential, anti-steatosis and anti-fibrosis effects in this NASH model
The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims. Any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other
combinations of the devices, systems, and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term“comprising” and variations thereof as used herein is used synonymously with the term“including” and variations thereof and are open, non-limiting terms. Although the terms“comprising” and“including” have been used herein to describe various embodiments, the terms“consisting essentially of’ and“consisting of’ can be used in place of“comprising” and“including” to provide for more specific embodiments of the invention and are also disclosed. Other than where noted, all numbers expressing geometries, dimensions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches.
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of skill in the art to which the disclosed invention belongs. Publications cited herein and the materials for which they are cited are specifically incorporated by reference.

Claims

WHAT IS CLAIMED IS:
1. A method for reducing fibrosis in a cell or tissue comprising contacting the cell or tissue with an estrogen receptor b (ERj3) agonist in an effective amount to decrease or inhibit the fibrosis.
2. A method of treating a fibrotic condition comprising administering an estrogen receptor b (ER{5) agonist to a subject in need thereof, in an effective amount to decrease or inhibit the fibrotic condition in the subject
3. The method of any of claims 1-2, wherein the ER 3 agonist comprises a compound defined by any of Formula I-Formula XXXIII.
4. The method of any of claims 1-3, wherein the ER 3 agonist comprises one of the following:
Figure imgf000081_0001
Figure imgf000082_0001
5. The method of any of claims 2-4, wherein treating the fibrotic condition comprises reducing or inhibiting one or more of: formation or deposition of tissue fibrosis; or reducing the size, cellularity, composition, cellular or collagen content, of a fibrotic lesion.
6. The method of any of claims 2-5, wherein the fibrotic condition is a fibrotic condition of the lung, a fibrotic condition of the liver, a fibrotic condition of the heart or vasculature, a fibrotic condition of the kidney, a fibrotic condition of the skin, a fibrotic condition of the gastrointestinal tract, a fibrotic condition of the bone marrow or hematopoietic tissue, a fibrotic condition of the nervous system, or a combination thereof.
7. The method of any of claims 2-6, wherein the fibrotic condition is secondary to an infectious disease, an inflammatory disease, an autoimmune disease, a connective disease, a malignant disorder or a clonal proliferative disorder; a toxin; an environmental hazard, cigarette smoking, a wound; or a medical treatment chosen from a surgical incision, chemotherapy or radiation.
8. The method of any of claims 2-6, wherein the fibrotic condition a fibrotic condition of the lung.
9. The method of claim 8, wherein the fibrotic condition of the lung is chosen from one or more of: pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), usual interstitial pneumonitis (UIP), interstitial lung disease, cryptogenic fibrosing alveolitis (CFA), or bronchiectasis.
10. The method of any of claims 2-6, wherein the fibrotic condition is a fibrotic condition of the liver.
11. The method of claim 10, wherein the fibrotic condition of the liver is chosen from fatty liver disease, steatosis, primary biliary cirrhosis (PBC), cirrhosis, alcohol induced liver fibrosis, biliary duct injury, biliary fibrosis, hepatic fibrosis associated with hepatitis infection, autoimmune hepatitis, non-alcoholic fatty liver disease (NAFLD), or progressive massive fibrosis.
12. The method of claim 10, wherein the fibrotic condition of the liver is chosen from nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
13. The method of any of claims 2-6, wherein the fibrotic condition is a fibrotic condition of the heart or vasculature.
14. The method of claim 13, wherein the fibrotic condition of the heart or vasculature is myocardial fibrosis.
15. The method of any of claims 2-6, wherein the fibrotic condition is a fibrotic condition of the kidney.
16. The method of claim 15, wherein the fibrotic condition of the kidney is chronic kidney fibrosis, nephropathies associated with injury/fibrosis, diabetic nephropathy, lupus, scleroderma of the kidney, glomerular nephritis, focal segmental glomerular sclerosis, IgA nephropathyrenal fibrosis associated with human chronic kidney disease (CKD), chronic progressive nephropathy (CPN), tubulointerstitial fibrosis, ureteral obstruction, chronic uremia, chronic interstitial nephritis, radiation nephropathy, glomerulosclerosis, progressive glomerulonephrosis (PGN), endothelial/thrombotic microangiopathy injury, or HIV- associated nephropathy.
17. The method of any of claims 2-6, wherein the fibrotic condition is a fibrotic condition of the skin.
18. The method of claim 17, wherein the fibrotic condition of the skin is selected from skin fibrosis, scleroderma, nephrogenic systemic fibrosis, and keloid.
19. The method of any of claims 2-6, wherein the fibrotic condition is a fibrotic condition of the gastrointestinal tract.
20. The method of claim 19, wherein the fibrotic condition of the gastrointestinal tract is diffuse scleroderma of the gastrointestinal tract.
21. The method of any of claims 2-6, wherein the fibrotic condition is a fibrotic condition of the bone marrow.
22. The method of claim 21, wherein the fibrotic condition of the bone marrow or hematopoietic tissue is chosen from one or more of: primary myelofibrosis; a fibrosis associated with a hematologic disorder chosen from polycythemia vera, essential thrombocythemia, myelodysplasia, hairy cell leukemia, lymphoma or multiple myeloma; a fibrosis of secondary to a non-hematologic disorder chosen from solid tumor metastasis to the bone marrow, an autoimmune disorder; an infection; or secondary hyperparathyroidism.
23. The method of any of claims 1-22, wherein the EίIb agonist exhibits an ERP-to-ERa agonist ratio of from 8 to 3000, such as an ERP-to-ERa agonist ratio of from 8 to 1500, from 1500 to 3000, from 400 to 3000, from 500 to 3000, from 600 to 3000, from 700 to 3000, from 800 to 3000, from 900 to 3000, from 1000 to 3000, or from 2000 to 3000.
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022117864A1 (en) 2020-12-03 2022-06-09 Delta 4 Gmbh Genistein for use in the treatment of focal segmental glomerulosclerosis (fsgs)
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
WO2022253884A1 (en) * 2021-06-02 2022-12-08 Axichem Ab Capsaicin derivatives in the treatment of idiopathic pulmonary fibrosis
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696433B2 (en) * 1996-07-22 2004-02-24 Renovo Limited Use of sex steroids function modulators to treat wounds and fibrotic disorders
US20150038468A1 (en) * 2009-07-28 2015-02-05 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Estrogen antagonists as treatments for sclerosing disorders

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696433B2 (en) * 1996-07-22 2004-02-24 Renovo Limited Use of sex steroids function modulators to treat wounds and fibrotic disorders
US20150038468A1 (en) * 2009-07-28 2015-02-05 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Estrogen antagonists as treatments for sclerosing disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PATEMI ET AL.: "Estrogen Receptors Alpha (ERalpha) and Beta (ERbeta): SubtypeSelective Ligands and Clinical Potential", NIH PUBLIC ACCESS, 15 November 2015 (2015-11-15), pages 1 - 45 *
PONNUSAMY ET AL.: "An estrogen receptor b-selective agonist inhibits non-alcoholic steatohepatitis in preclinical models by regulating bile acid and xenobiotic receptors", EXPERIMENTAL BIOLOGY AND MEDICIN E, vol. 242, March 2017 (2017-03-01), pages 606 - 616, XP055729971 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11944622B2 (en) 2018-10-05 2024-04-02 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
WO2022117864A1 (en) 2020-12-03 2022-06-09 Delta 4 Gmbh Genistein for use in the treatment of focal segmental glomerulosclerosis (fsgs)
WO2022253884A1 (en) * 2021-06-02 2022-12-08 Axichem Ab Capsaicin derivatives in the treatment of idiopathic pulmonary fibrosis
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

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