WO2020231909A1 - Compositions and methods for treating bile acid associated diseases - Google Patents
Compositions and methods for treating bile acid associated diseases Download PDFInfo
- Publication number
- WO2020231909A1 WO2020231909A1 PCT/US2020/032322 US2020032322W WO2020231909A1 WO 2020231909 A1 WO2020231909 A1 WO 2020231909A1 US 2020032322 W US2020032322 W US 2020032322W WO 2020231909 A1 WO2020231909 A1 WO 2020231909A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tyrosine
- methyl
- bile acid
- treating
- disorder
- Prior art date
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 132
- 239000003613 bile acid Substances 0.000 title claims abstract description 122
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 title claims abstract description 96
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- 230000007306 turnover Effects 0.000 description 1
- INASOKQDNHHMRE-UHFFFAOYSA-N turofexorate isopropyl Chemical compound C1C(C)(C)C(C2=CC=CC=C2N2)=C2C(C(=O)OC(C)C)=CN1C(=O)C1=CC=C(F)C(F)=C1 INASOKQDNHHMRE-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009777 vacuum freeze-drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
- 150000003710 vitamin D derivatives Chemical class 0.000 description 1
- 229940046008 vitamin d Drugs 0.000 description 1
- 229940111503 welchol Drugs 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229930007845 β-thujaplicin Natural products 0.000 description 1
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
Definitions
- the invention relates to compositions and methods for treating bile acid associated diseases. Specifically, the invention relates to treating bile acid associated diseases by administering a tyrosine hydroxylase inhibitor.
- Bile acids are steroid acids molecules synthesized from cholesterol which were historically considered to arise exclusively in the liver. However, recent studies show that bile acids are the prominent steriod in the brain and may be synthecized in the brain.
- Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans.
- Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators, in effect acting like steroid hormones.
- Such regulatory function of bile acids is in part a result of bile acid activation of various intracellular ligand-activated nuclear receptors, such as the famesoid X receptor (FXR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), and vitamin D receptor (VDR), and cell surface G protein-coupled receptors (GPCRs), such as the G protein-coupled bile acid receptor (TGR5 and Gpbar-1). These receptors bind the retinoid receptor and when activated by bile acids can migrate to the nucleus and modulate transcription.
- FXR famesoid X receptor
- PXR pregnane X receptor
- Bile acids are synthesized from cholesterol in specialized cells, called hepatocytes, which are located in distinct liver domains termed lobules. Bile synthesis is carried out through a complex pathway requiring 17 individual enzymes and occurring in multiple intracellular compartments that include the cytosol, endoplasmic reticulum (ER), mitochondria, and peroxisomes. Bile formation starts with secretion of bile salts into the bile canaliculi, via the action of the bile salt export protein (BSEP). The mixture of secreted bile salts is then transported, through the canaliculi, into the gall bladder, where they are concentrated to form bile.
- BSEP bile salt export protein
- bile acids are cytotoxic their synthesis and secretion is tightly controlled through several mechanisms.
- One of these mechanisms is the auto-regulation of bile acid synthesis and release, primarily through FXR-mediated inhibition, of hepatic CYP7A1 enzyme activity at the transcriptional level.
- FXR hepatic CYP7A1 enzyme activity
- bile acids can impact triglyceride metabolism, glucose metabolism and cholesterol and lipid metabolism, and dysregulation of bile acid metabolism (and resulting alteration of bile acid pool size and composition) has been suggested as one of contributing causes of diabetes.
- bile acid synthesis is regulated by insulin and glucose and reciprocally regulates these agents.
- insulin was shown to repress the expression of FXR gene suggesting that diabetes may be associated with dysregulation of FXR gene expression, and bile salt stimulated FXR has been shown to induce insulin secretion.
- Bile secretion is also regulated by food intake on multiple levels. On one level, consumption of lipid triggers secretion of the hormone cholecystokinin (CCK) by enteroendocrine I cells in the duodenum. CCK enters the circulation and binds to receptors on the gall bladder, thus promoting contraction of smooth muscle cells of the gall bladder and relaxation of the sphincter of Oddi, leading to the pulsatile secretion of bile into the duodenum.
- CCK cholecystokinin
- Another proposed mechanism of bile flow regulation by autonomous nervous system involves prostaglandins. Stimulating of the sympathetic liver nerves with electrical signal in the perfused rat liver, resulted in reduction bile flow and bile acid secretion by way of al- adrenergic receptors. On the other hand administering prostaglandin FZ ,a systemically resulted in stimulation of bile flow.
- Bile acids bind to other proteins in addition to their hormone receptors (e.g. FXR and TGR5) and their transporters.
- FXR and TGR5 hormone receptors
- TGR5 TGF receptors
- the enzyme N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) generates bioactive lipid amides (e.g. the endogenous cannabinoid anandamide) that play important roles in several physiological pathways including stress and pain responses, appetite, and lifespan.
- NAPE-PLD N-acyl phosphatidylethanolamine-specific phospholipase D
- bile acids are further modified into structurally diverse secondary bile acid species by gut microbiota. Different primary and secondary bile acid species exhibit different capacities to bind and activate FXR, making bile acid composition a crucial factor for determining FXR activity in various tissues.
- Bile salts are believed to be the primary steroid in the brain, and while bile salt metabolism in the liver is well- studied, little is known about it behind the blood-brain barrier. These processes however may be highly significant, since at least one bile acid receptor, TGR5, has been shown to be involved in bile acid mediated signaling in the brain, and may mediate bile acid-induced itch and analgesia associated with cholestasis.
- TGR5 bile acid receptor
- Another possible pathway of the bile acids action in central nervous system involves FXR-mediated induction of FGF15/19, which was recently shown to regulate metabolism by acting on the brain.
- bile acid activity in the brain raises the possibility of cross talk between neurosteroids and bile acids, possibly to alter neurotransmission.
- Neurosteroids classically act to modulate GABAergic tone, and in fact, the bile acids, ursodeoxycholic acid (UDCA) and chenodeoxy cholic acid (CDCA), have been shown recently to antagonize GABAA receptors, and CDCA was shown to antagonize NMDA receptors.
- UDCA ursodeoxycholic acid
- CDCA was shown to antagonize NMDA receptors.
- the possiblities exist that control of bile acids may have a central regulatory component and/or central bile acid metabolism may have a peripheral component.
- AD Alzheimer’s disease
- apolipoprotem E the most common genetic risk factor for AD
- amyloid plaques formation apolipoprotem E
- CUMS chronic unpredictable mild stress
- an animal model of depression resulted in significant biochjemical changes in the liver, specifically altered expression profile of Pla2gl5, Pnpla6, Baat and Gadl, four key enzymes involved in phospholipid and primary bile acid biosynthesis in liver.
- tauroursodeoxy cholic acid a hydrophilic bile acid that is produced in the liver
- bile acids were found to exert neuroprotective effects in models of Huntington’s disease.
- TUDCA was shown to be an effective treatment of amyotrophic lateral sclerosis.
- Bile salts are implicated as having roles in various additional conditions including autism, diabetes, fibromyalgia, post traumatic stress disorder (PTSD), and others. Moreover, the synthesis and release of bile acids is regulated by autonomic nervous system (ANS), in part as a function of circadian rhythm. As such bile acids may mediate metabolic diseases that result from disruption of circadian regulation.
- ANS autonomic nervous system
- the invention relates to a method for treating a bile acid associated disease or disorder in a subject in need thereof, the method comprising: administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said bile acid associated disease or disorder in said subject.
- a tyrosine hydroxylase inhibitor is racemic a-methyl-DL-tyrosine.
- the invention in another aspect, relates to a composition comprising a tyrosine hydroxylase inhibitor, wherein said tyrosine hydroxylase inhibitor is present in an amount effective to treat a bile acid associated disease or disorder in a subject.
- the invention relates to a method for treating a bile acid associated disease or disorder in a subject in need thereof, the method comprising: administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor in combination with another treating agent (e.g., another agent that treats bile acid associated disease or disorder), thereby treating said bile acid associated disease or disorder in said subject.
- another treating agent e.g., another agent that treats bile acid associated disease or disorder
- the invention relates to a composition comprising a tyrosine hydroxylase inhibitor in combination with another treating agent, wherein said tyrosine hydroxylase inhibitor and said another treating agent are present in an amount effective to treat a bile acid associated disease or disorder in a subject.
- the invention relates to a method of treating a bile acid- associated pathological cognitive condition in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said pathological cognitive condition.
- the invention relates to a method of treating a bile acid- associated neurodegenerative disorder in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said neurodegenerative disorder.
- the invention relates to a method of treating bile acid- associated neuronal damage, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said neuronal damage.
- the invention relates to a method of treating a bile acid- associated diabetes in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating a said diabetes.
- the invention relates to a method of treating a bile acid- associated central nervous system (CNS) disease or disorder, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said CNS disease or disorder.
- CNS central nervous system
- the invention relates to a method of treating a disease or disorder associated with bile acid-mediated lipid metabolism, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said disease or disorder.
- the terms “component,” “composition,” “composition of compounds,” “compound,” “drug,” “pharmacologically active agent,” “active agent,” “therapeutic,” “therapy,” “treatment,” or “medicament” are used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to a subject (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action.
- treatment or “therapy” (as well as different forms thereol) include preventative (e.g., prophylactic), curative or palliative treatment.
- the term “treating” includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder. This condition, disease or disorder can be acne or its related skin condition.
- stereoisomers refers to compounds that have identical chemical constitution, but differ as regards the arrangement of the atoms or groups in space.
- enantiomers refers to stereoisomers that are mirror images of each other that are non- superimposable.
- subject refers to an animal, for example a human, to whom treatment, including prophylactic treatment, with the pharmaceutical composition according to the present invention, is provided.
- subject refers to human and non-human animals.
- inhibitor includes compounds that inhibit the expression or activity of a protein, polypeptide or enzyme and does not necessarily mean complete inhibition of expression and/or activity. Rather, the inhibition includes inhibition of the expression and/or activity of a protein, polypeptide or enzyme to an extent, and for a time, sufficient to produce the desired effect.
- a method of treatment of bile acid- associated disease or disorder in a subject comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
- tyrosine hydroxylase inhibitors function by decreasing the functional amount of catecholamine neurotransmitters, including adrenaline, secreted into the bloodstream.
- Catecholamine neurotransmitters activate sympathetic nervous system, and its improper activation in turn results in excessive bile production and secretion.
- bile acids are under the control of the autonomic nervous system and the balance sympathetic and parasympathetic afferent neurotransmission.
- tyrosine hydroxylase treatment works to suppress sympathetic nervous system signaling and prevent or reverse excessive bile production and secretion, and the inhibition of tyrosine hydroxylase activity can serve to adjust the balance between the arms of the autonomic nervous system.
- a method of altering bile acids metabolism in a subject comprising prevention of activation of sympathetic nervous system activation in said subject, through administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
- Excessive bile production and secretion described above leads to multiple pathologies, including, without limitation, central nervous system disorders, peripheral nervous system disorders, and metabolic disorders. Elevated bile acids levels results in suppression of GABA and NMDA receptor signaling (by bile acids ursodeoxycholic acid (UDCA) and chenodeoxy cholic acid (CDCA)). Thus, the modulation of tyrosine hydroxylase may work to restore GABA and NMDA receptor signaling, thereby preventing or suppressing development of a cognitive condition, such as Alzheimer's disease, autism or PTSD. Excessive bile acids also disrupt blood brain barrier and enter the brain, ultimately causing brain damage and subsequent neurological decline. Tyrosine hydroxylase treatment may work to restore normal levels of bile production and bile acid concentration in serum, thereby preventing neuronal damage.
- GABA and NMDA receptor signaling by bile acids ursodeoxycholic acid (UDCA) and chenodeoxy cholic acid (CDCA)
- FXR activation also induces proliferator-activated receptors (PPARs), which, inter alia, modulate triglyceride (TG) production.
- PPARs proliferator-activated receptors
- TG triglyceride
- Dysregulation of PPARs have been shown to cause behavioral phenotype of cognitive inflexibility, perseveration, blunted responses to psychomimetic drugs, as well as development of other autism- like symptoms in animal models.
- tyrosine hydroxylase treatment may work to restore normal levels of FXR and PPAR- a, thereby restoring normal neurological function.
- a method of treating a bile acid- associated pathological cognitive condition or a neurodegenerative condition in a subject comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
- the present invention further provides for a method of treating a bile acid- associated neuronal damage, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
- a method of treating a bile acid-associated central nervous system (CNS) disease or disorder comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
- CNS central nervous system
- FXR activation inhibits the induction of glucose-responsive genes, such as L-type pyruvate kinase (L-PK), resulting in reduced glucose sensitivity.
- L-PK L-type pyruvate kinase
- tyrosine hydroxylase treatment may work to restore normal levels of FXR, PEPCK and L-PK activity, thereby lowering glucose levels and restoring normal glucose metabolism.
- a method of treating of a bile acid associated metabolic syndrome comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
- a method of treating of diabetes in a subject comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor that influences bile acid release and subsequent orphan receptor function resulting in an increase in insulin sensitivity.
- provided herein is a method of treating a disease or disorder associated with bile acid-mediated lipid metabolism, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
- the tyrosine hydroxylase inhibitor is well known in the art and fully described in, for example, U.S. Patent Application Publications US 2015/0290279, US 2015/0216827, US 2015/0111937, US 2015/0111878, US 2013/0184214, and US 20130183263; U.S. Patents US 8,481,498, US 9,308,188, and US 9,326,962; and PCT Patent Application Publication WO2015061328, which are incorporated by reference herein in their entirety. Any suitable tyrosine hydroxylase inhibitor, known to one of skilled in the art, can be used.
- the tyrosine hydroxylase inhibitor is a tyrosine derivative.
- the tyrosine derivative can be capable of existing in different isomeric forms, including stereoisomers and enantiomers.
- the tyrosine derivative can, for example, exist in both L-form or D-form.
- the tyrosine derivative can, for example, also exist in a racemic form.
- Representative tyrosine derivatives include, for example, one or more of methyl (2R)-2-amino-3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2- amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate H-D-tyrosine(tBu)- allyl ester hydrochloride, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2- amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino- 3-(2-chloro-3,4-d
- the tyrosine derivative is a-methyl-D-tyrosine. In other embodiments, the tyrosine derivative is a-methyl-DL-tyrosine in a racemic form as shown below:
- the tyrosine derivative is a structural variant of a- methyl-L-tyrosine or a-methyl-DL-tyrosine.
- the structural variants of a-methyl-L-tyrosine or a-methyl-DL-tyrosine are well known in the art and fully described in, for example, U. S. Patent 4, 160,835, which is incorporated by reference herein in its entirety.
- the tyrosine derivative of the invention is an arylalanine compound having the formula:
- Ri is hydrogen, methyl or ethyl ester group, or alkyl of from 1 to 4 carbon atoms
- R 2 is hydrogen, lower alkyl, lower alkene, succinimide, or alkyl of from 1 to 4 carbon atoms
- R3 is a substituted benzene ring of the following general formula
- Y 1 is located at the para position and is hydrogen, hydroxy, methyl ether, dimethyl ether, trimethyl ether, or an unsubstituted or halogen-substituted benzyl
- Y 2 , and Y3 are the same or different and wherein one or both Y 2 , and Y3 located at either meta position or ortho position, and wherein Y 2 , and Y3 are hydrogen, hydroxy, halogen, methyl ether, or nitro
- R4 is hydrogen, acetyl, tert-butyloxycarbonyl or fluorenylmethyloxy carbonyl.
- Y1 and Y2 are the same or different and are selected from hydrogen, cyanoamino, carboxyl, cyano, thiocarbamoyl, aminomethyl, guanidino, hydroxy, methanesulfonamido, nitro, amino, methanesulfonyloxy, carboxymethoxy, formyl, methoxy and a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing carbon and one or more nitrogen, sulfur or oxygen atoms, specific examples of such heterocyclic rings being pyrrol-l-yl, 2-carboxypyrrol-l-yl, imidazol-2-ylamino, indol-l-yl, carbazol-9-yl, 4,5-dihydro-4-hydroxy-4-trifluoromethylthiazol-3-yl, 4-trifluoromethylthiazol- 2-yl, imidazol-2-yl and 4,5-di
- R3 is a substituted or unsubstituted benzoheterocyclic ring having the formula:
- the benzoheterocyclic ring is selected from the group consisting of indolin-5-yl, 1- (N-benzoylcarbamimidoyl)-indolin-5-yl, l-carbamimidoylindolin-5-yl, 1 H-2-oxindol-5-yl, indol-5-yl, 2-mercaptobenzimidazol-5(6)-yl, 2-aminobenzimidazol-5(6)-yl, 2- methanesulfonamido-benzimidazol-5(6)-yl, 1 H-benzoxazol-2-on-6-yl, 2-aminobenzothiazol- 6-yl, 2-amino-4-mercaptobenzothiazol-6-yl, 2,l,3-benzothiadiazol-5-yl, l,3-dihydro-2,2- dioxo-2,l,3-benzothiadiazol-5-yl, l,3-dihydro-l,3-di
- R3 is a substituted or unsubstituted heterocyclic ring having the formula:
- heterocyclic ring is selected from the group consisting of 5- hydroxy-4 H-pyran-4-on-2-yl, 2-hydroxypyrid-4-yl, 2-aminopyrid-4-yl, 2-carboxypyrid-4-yl, or tetrazolo[l,5-a]pyrid-7-yl.
- the tyrosine hydroxylase inhibitor is aquayamycin.
- aquayamycin is a compound of the formula set forth below.
- the tyrosine hydroxylase inhibitor is oudenone.
- oudenone is a compound of the formula set forth below.
- tyrosine hydroxylase inhibitor known to one of skilled in the art
- tyrosine hydroxylase inhibitor include, for example, but not limited to, cycloheximide, anisomycin, 3-iodo-L-tyrosine, pyratrione, phenyl carbonyl derivatives having catechol or triphenolic ring systems, for example, phenethylamine and gallic acid derivatives, 4-isopropyltropolone, 2-(4 -thiazolyl)benzimidazole, 8-hydroxyquinoline, o- phenantroline, 5-iodo-8-hydroxyquinoline, bilirubin, 2,9-dimethyl- 1, 10- phenantroline, a-a’- dipyridil, dibenzo [/./tlquinoxaline.
- the invention relates administering a therapeutically effective amount of another agent useful in the treatment of a bile acid associated disease or disorder.
- another agent useful in the treatment of a bile acid associated disease or disorder include, for example, but not limited to, an agent for treating a bile acid synthesis disorder, a bile acid sequestrant, a bile acid binding agent, and an agent for treating bile acid reflux.
- an agent for treating a bile acid synthesis disorder include, but not limited to, Cholbam (cholic acid), which treats a rare bile acid synthesis disorder.
- Examples of a bile acid sequestrant include, but not limited to, cholestyramine (Questran, Prevalite), colestipol (Colestid, Flavored Colestid), and colesevelam (Welchol), and medications for lowering LDL cholesterol in conjunction with diet modification.
- Examples of a bile acid binding agent include, but not limited to, cholestyramine (such as Prevalite) and colestipol.
- Examples of an agent that treats bile acid reflux include, but not limited to, ursodeoxycholic acid which helps promote bile flow; bile acid sequestrants; and proton pump inhibitors, which block acid production.
- bile acid associated disease or disorder examples include, for example, but not limited to, steroidal or nonsteroidal agonists of FXR and TGR5.
- the semi-synthetic bile acid obeticholic acid (6-ethyl-CDCA, INT-747) and non-steroidal compounds PX-102 and WAY-362450 are examples for FXR agonists.
- the invention also provides a pharmaceutical composition
- a pharmaceutical composition comprising compounds of the invention and one or more pharmaceutically acceptable carriers.
- “Pharmaceutically acceptable carriers” include any excipient which is nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed.
- the pharmaceutical composition may include one or additional therapeutic agents.
- “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable carriers include solvents, dispersion media, buffers, coatings, antibacterial and antifungal agents, wetting agents, preservatives, buggers, chelating agents, antioxidants, isotonic agents and absorption delaying agents.
- Pharmaceutically acceptable carriers include water; saline; phosphate buffered saline; dextrose; glycerol; alcohols such as ethanol and isopropanol; phosphate, citrate and other organic acids; ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; EDTA; salt forming counterions such as sodium; and/or nonionic surfactants such as TWEEN, polyethylene glycol (PEG), and PLURONICS; isotonic agents such as sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride; as well as combinations
- the disclosed compounds may be prepared in the form of pharmaceutically acceptable salts.
- “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
- Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
- the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
- inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
- organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
- physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.
- Compounds described herein can be prepared in alternate forms. For example, many amino-containing compounds can be used or prepared as an acid addition salt. Often such salts improve isolation and handling properties of the compound. For example, depending on the reagents, reaction conditions and the like, compounds as described herein can be used or prepared, for example, as their hydrochloride or tosylate salts. Isomorphic crystalline forms, all chiral and racemic forms, N-oxide, hydrates, solvates, and acid salt hydrates, are also contemplated to be within the scope of the present invention.
- Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated to be within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxy groups often exist in equilibrium with their zwitterionic forms. Thus, any of the compounds described herein that contain, for example, both amino and carboxy groups, also include reference to their corresponding zwitterions.
- compositions of the invention may be formulated in a variety of ways, including for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories.
- the compositions are in the form of injectable or infusible solutions.
- the composition is in a form suitable for oral, topical, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, transmucosal, or transdermal administration.
- the composition may be formulated as an immediate, controlled, extended or delayed release composition.
- Preparations for administration may also include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
- non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
- pharmaceutically acceptable carriers include, but are not limited to, 0.01-0.1M and preferably 0.05M phosphate buffer or 0.8% saline.
- Intravenous vehicles include sodium phosphate solutions, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as for example, antimicrobials, antioxidants, chelating agents, and inert gases and the like.
- compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
- the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and will preferably be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
- the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
- the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
- a coating such as lecithin
- surfactants Suitable formulations for use in the therapeutic methods disclosed herein are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., 16th ed. (1980).
- the composition includes isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride.
- Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
- Sterile solutions can be prepared by incorporating the molecule, by itself or in combination with other active agents, in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization.
- dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above.
- sterile powders for the preparation of sterile injectable solutions one method of preparation is vacuum drying and freeze-drying, which yields a powder of an active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
- the preparations for injections are processed, filled into containers such as ampoules, bags, bottles, syringes or vials, and sealed under aseptic conditions according to methods known in the art. Further, the preparations may be packaged and sold in the form of a kit such as those described in US Appl. Publ. No. 2002/0102208 Al, which is incorporated herein by reference in its entirety. Such articles of manufacture will preferably have labels or package inserts indicating that the associated compositions are useful for treating a subject suffering from, or predisposed to autoimmune or neoplastic disorders.
- Effective doses of the compositions of the present invention, for treatment of conditions or diseases as described herein vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic.
- the patient is a human but non-human mammals including transgenic mammals can also be treated.
- Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
- the pharmaceutical compositions of the invention may include a“therapeutically effective amount.”
- A“therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
- a therapeutically effective amount of a molecule may vary according to factors such as the disease state, age, sex, and weight of the individual, and the ability of the molecule to elicit a desired response in the individual.
- a therapeutically effective amount is also one in which any toxic or detrimental effects of the molecule are outweighed by the therapeutically beneficial effects.
- the dosage of tyrosine hydroxylase inhibitor may range from about 1 mg to about 4g. In a particular embodiment, the dosage of tyrosine hydroxylase inhibitor may range from about 3 mg to about 1000 mg. In some suitable embodiments of the invention, 25 mg of the tyrosine hydroxylase inhibitor is administered. In one example, 60 mg of the tyrosine derivative can be administered orally. In another example, 0.25 mL of a 2 mg/mL suspension of the tyrosine derivative can be administered subcutaneously.
- the dosage of another agent useful in the treatment of a bile acid associated disease or disorder may include a therapeutically effective or clinically acceptable amount.
- the dosage of another agent is an amount that complements with or enhances the effect of a tyrosine hydroxylase inhibitor described herein.
- the terms“treat” and“treatment” refer to therapeutic treatment, including prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change associated with a disease or condition.
- Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, amelioration or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition, whether detectable or undetectable.
- Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in which the disease or condition is to be prevented.
- the diseases or disorders treated by the composition of the invention include, for example, a bile acid associated disease or disorder.
- a bile acid associated disease or disorder include, for example, but not limited to, stress; glucose metabolism disorders, such as insulin sensitivity, hyperglycemia, hypertriglyceridemia, diabetes, obesity & related events , for example coronary disease and atherosclerosis; central nervous system disorders, such as amyotrophic lateral sclerosis, encephalopathy, Alzheimer’s Disease, Huntington’s disease, autism, sensory transduction, neuromyelitis optica, depression, cerebrotendinous xanthomatosis, fibromyalgia, post traumatic stress disorder (PTSD), and dementia; psychotic disorders, for example, bipolar disorder and schizophrenia; lipid metabolism disorders, for example, hyperlipidemia, dyslipidemia, hypercholesterolemia, fatty liver disease; and multiple additional disorders, such as gallstones, colon cancer, inflammatory bowel disease, liver fibrosis, alcoholic liver disease, hypertension, acute
- the invention provides administering to a subject a therapeutically effective amount of a first tyrosine hydroxylase inhibitor, for example, a-methyl-DL-tyrosine in combination with a therapeutically effective amount of a second tyrosine hydroxylase inhibitor, for example, a-methyl-L-tyrosine.
- a therapeutically effective amount of one or more tyrosine hydroxylase inhibitors for example, a-methyl-DL-tyrosine and/or a-methyl-L-tyrosine in combination with a therapeutically effective amount of another agent useful in the treatment of a bile acid associated disease or disorder.
- the invention provides a composition comprises a tyrosine hydroxylase inhibitor, wherein said tyrosine hydroxylase inhibitor is present in an amount effective to treat a bile acid associated disease or disorder in a subject.
- the tyrosine hydroxylase inhibitor is a-methyl-DL-tyrosine.
- the composition further comprises a therapeutically effective amount of another tyrosine hydroxylase inhibitor, for example, metyrosine or a-methyl-L-tyrosine.
- the composition further comprises a therapeutically effective amount of another agent, known to one of skilled in the art, useful in the treatment of a bile acid associated disease or disorder.
- a tyrosine hydroxylase inhibitor or a composition described above can be administered with another treating agent (e.g., another agent that treats a bile acid associated disease or disorder), known in the art, for example, but not limited to, an agent for treating a bile acid synthesis disorder, a bile acid sequestrant, a bile acid binding agent, and an agent for treating bile acid reflux.
- another treating agent e.g., another agent that treats a bile acid associated disease or disorder
- another treating agent e.g., another agent that treats a bile acid associated disease or disorder
- a tyrosine hydroxylase inhibitor or a composition described above can be administered in combination with another treatment procedure, known to one of skilled in the art.
- Administration of the tyrosine hydroxylase inhibitor or the tyrosine hydroxylase inhibitor and the another agent can be through various routes, including orally, topically, subcutaneously, intravenously, intramuscularly, transdermally, or in any combination thereof.
- tyrosine hydroxylase inhibitor is co-administered with another treating agent.
- tyrosine hydroxylase inhibitor is administered independently from the administration of another treating agent.
- tyrosine hydroxylase inhibitor is administered first, followed by the administration of another treating agent.
- said another treating agent is administered first, followed by the administration of said tyrosine hydroxylase inhibitor.
- a tyrosine hydroxylase can be combined with an agent which stimulates endogenous bile acid release such as estradiol.
- tyrosine hydroxylase inhibitor administered to another treating agent and/or other treatments may occur simultaneously, or separately, via the same or different route, at the same or different times. Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response).
- a single bolus may be administered.
- several divided doses may be administered over time.
- a dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
- Dosage unit form refers to physically discrete units suited as unitary dosages for treating mammalian subjects. Each unit may contain a predetermined quantity of active compound calculated to produce a desired therapeutic effect. In some embodiments, the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic or prophylactic effect to be achieved.
- composition of the invention may be administered only once, or it may be administered multiple times.
- the composition may be, for example, administered three times a day, twice a day, once a day, once every two days, twice a week, weekly, once every two weeks, or monthly.
- dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
- administering to a subject is not limited to any particular delivery system and may include, without limitation, oral (for example, in capsules, suspensions or tablets), parenteral (including subcutaneous, intravenous, intramedullary, intraarticular, intramuscular, or intraperitoneal injection), topical, or transdermal.
- Administration to a host may occur in a single dose or in repeat administrations, and in any of a variety of physiologically acceptable salt forms, and/or with an acceptable pharmaceutical carrier and/or additive as part of a pharmaceutical composition (described earlier).
- physiologically acceptable salt forms and standard pharmaceutical formulation techniques are well known to persons skilled in the art (see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co.).
- composition of the invention may be administered topically or orally.
- the composition of the invention may also be administered parenterally (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). Further, the composition of the invention may be administered by intravenous infusion or injection.
- the composition of the invention may be administered by intramuscular or subcutaneous injection.
- the composition of the invention may be administered by any suitable route known to one of skilled in the art.
- a "composition” refers to any composition that contains a pharmaceutically effective amount of one or more active ingredients (e.g., a tyrosine hydroxylase inhibitor, another acne treating agent, or a combination thereol).
- a method for diagnosing a bile acid associated disease or disorder in a subject comprising: obtaining a biological sample from said subject; determining the presence or absence of a polymorphism in cytochrome P450 3A4 (CYP3A4) in said sample, wherein the presence of said polymorphism in said sample indicates the presence of said disease in said subject.
- the invention relates to treating a bile acid associated disease or disorder based on the determination of the polymorphism in CYP3A4.
- Cytochrome P450 3A4 (CYP3A4), is a member of cytochrome 450 superfamily of monooxygenase enzymes and is mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. This enzyme is involved in the metabolism of approximately half the drugs in use today, including acetaminophen, codeine, cyclosporin A, diazepam and erythromycin. The enzyme also metabolizes some steroids and carcinogens.
- CYP3A4 is predominantly found in the liver, it is also present in other organs and tissues of the body, where it may play an important role in metabolism. In the intestine, CYP3A4, CYP2B, CYP2C, and epimerases are involved in detoxification of LCA to more soluble hyocholic acid and ursodeoxycholic acid (UDCA) in humans. CYP3A4 also possesses epoxygenase activity in that it metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs). Recently CYP3A4 has also been identified in the brain, however its role in the central nervous system is still unknown.
- CYP3A4 is induced by a wide variety of ligands. These ligands bind to the pregnane X receptor (PXR). The activated PXR complex forms a heterodimer with the retinoid X receptor (RXR), which binds to the XREM region of the CYP3A4 gene.
- PXR pregnane X receptor
- RXR retinoid X receptor
- CYP3A4 availability is mediated by bile acids (via a feedback regulatory loop operating through VDR-mediated signaling), certain corticosteroids, vitamin D, androstane, estrogens, as well as multiple other endogenous compounds and xenobiotics. Finally its levels are subject to circadian cycle.
- the polymorphism in CYP3A4 can be any type of polymorphism, known to one of skilled in the art.
- the polymorphism is a single-nucleotide polymorphism (SNP), known to one of skilled in the art.
- a single-nucleotide polymorphism is a variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population. While rarely altering function of proteins encoded by the genes where SNPs occur, they are known to associate with various phenotypic traits, including diseases such as cancer. Genetic association studies of SNPs have identified numerous examples of association between SNPs and different pathologies. This makes SNPs a potentially valuable diagnostic tool, and discovery of novel SNP-pathology association a promising area of research.
- SNP detection includes dynamic allele-specific hybridization, use of molecular beacons and SNP microarrays, restriction fragment length polymorphism analysis, PCR-based analysis, FLAP endonuclease assays, primer extension assays, 5’- nuclease assay, oligonucleotide ligation assay, single strand conformation polymorphism assay, temperature gradient gel electrophoresis, high resolution melting analysis, use of DNA mismatch-binding proteins, surveyor nuclease assay, high throughput sequencing, among others.
- SNPs single nucleotide polymorphisms
- the polymorphism in CYP3A4 can be detected by any suitable method known to one of skilled in the art, for example, but not limited to, a polymerase chain reaction (PCR) based method, a microarray based method, a sothem blotting, a western blotting, an in situ hybridisation, and other methods known in the art.
- PCR polymerase chain reaction
- subject may refer to any suitable mammal, including primates, such as monkeys and humans, horses, cows, cats, dogs, rabbits, and rodents such as rats and mice.
- the subject is a human subject.
- composition having a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles.
- the symptoms can be monitored for all subjects biweekly.
- composition having a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- the assessment can include social initiations, play, gestures, requests, eye contact, joint attention, etc. pressed for, observed, and coded by examiner.
- ADOS Autism Diagnostic Observational Schedule
- an examiner pulls for target behaviors through specific use of toys, activities, and interview questions; and stereotypical behaviors, sensory sensitivities, aberrant behaviors and the like are also observed and coded.
- Autism Diagnostic Observational Schedule typically requires about 30-60 minutes of observation, followed by about 15 minutes of scoring; utilizes 29 questions, of which 12-14 are used for scoring; and requires about 60-90 minutes for total assessment.
- ADOS-G Autism Diagnostic Observational Schedule-Generic exam is divided into four modules.
- Module 1 is geared towards a specific group of individuals based on their level of language and to ensure coverage for wide variety of behavioral manifestations.
- Module 1 containing 10 activities and 29 items, is focused on individuals with little or no language and therefore most typical for assessment of younger children.
- Non-psychogenic assessments of autistim related symptoms such as effects on digestion, elimination, sleep, or other manifestations of autism can be assessed.
- composition having a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a patient in single or divided doses between 50-1500 mg.
- composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles.
- the diabetes symptoms such as blood glucose levels, can be monitored for all subjects biweekly through fasting plasma glucose (FPG) test, the AIC test, or random plasma glucose (RPG) test.
- FPG fasting plasma glucose
- AIC AIC
- RPG random plasma glucose
- composition having a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a patient in single or divided doses between 50-1500 mg.
- composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles.
- the PTSD symptoms can be monitored for all subjects biweekly through, for example evaluation under Structured Interview for PTSD (SI-PTSD; Davidson et al, J Nervous Mental Disease 177:336-41 (1989)), the Clinician Administered PTSD Scale (CAPS; Blake et al, Behavior Therapist 13: 187-8 (1990)) or the Short Screening Scale for DSM-IV PTSD (Breslau et al, Am J Psychiatry 156:908-11 (1999)).
- composition having a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a patient in single or divided doses between 50-1500 mg.
- composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles.
- the symptoms can be monitored for all subjects biweekly.
- composition having a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a patient in single or divided doses between 50-1500 mg.
- composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles.
- the symptoms can be monitored for all subjects biweekly.
- composition having a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a patient in single or divided doses between 50-1500 mg.
- composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles.
- the symptoms can be monitored for all subjects biweekly.
- composition having a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a patient in single or divided doses between 50-1500 mg.
- composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles.
- the symptoms can be monitored for all subjects biweekly.
- composition having a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a patient in single or divided doses between 50-1500 mg.
- composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles.
- the symptoms can be monitored for all subjects biweekly.
- composition having a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a tyrosine hydroxylase inhibitor e.g., a-methyl-DL tyrosine
- a patient in single or divided doses between 50-1500 mg.
- composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles.
- the symptoms can be monitored for all subjects biweekly.
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Abstract
The invention relates to compositions and methods for treating a bile acid associated disease or disorder. Specifically, the invention relates to treating a bile acid associated disease or disorder by administering a tyrosine hydroxylase inhibitor.
Description
COMPOSITIONS AND METHODS FOR TREATING BILE ACID ASSOCIATED
DISEASES
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No. 62/846,630, filed May 11, 2019, the entirety of which is incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The invention relates to compositions and methods for treating bile acid associated diseases. Specifically, the invention relates to treating bile acid associated diseases by administering a tyrosine hydroxylase inhibitor.
BACKGROUND OF THE INVENTION
[0003] Bile acids are steroid acids molecules synthesized from cholesterol which were historically considered to arise exclusively in the liver. However, recent studies show that bile acids are the prominent steriod in the brain and may be synthecized in the brain.
[0004] Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators, in effect acting like steroid hormones. Such regulatory function of bile acids is in part a result of bile acid activation of various intracellular ligand-activated nuclear receptors, such as the famesoid X receptor (FXR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), and vitamin D receptor (VDR), and cell surface G protein-coupled receptors (GPCRs), such as the G protein-coupled bile acid receptor (TGR5 and Gpbar-1). These receptors bind the retinoid receptor and when activated by bile acids can migrate to the nucleus and modulate transcription.
[0005] Bile acids are synthesized from cholesterol in specialized cells, called hepatocytes, which are located in distinct liver domains termed lobules. Bile synthesis is carried out through a complex pathway requiring 17 individual enzymes and occurring in multiple intracellular compartments that include the cytosol, endoplasmic reticulum (ER), mitochondria, and peroxisomes. Bile formation starts with secretion of bile salts into the bile canaliculi, via the action of the bile salt export protein (BSEP). The mixture of secreted bile salts is then
transported, through the canaliculi, into the gall bladder, where they are concentrated to form bile.
[0006] Because bile acids are cytotoxic their synthesis and secretion is tightly controlled through several mechanisms. One of these mechanisms is the auto-regulation of bile acid synthesis and release, primarily through FXR-mediated inhibition, of hepatic CYP7A1 enzyme activity at the transcriptional level. Additionally, through FXR, bile acids can impact triglyceride metabolism, glucose metabolism and cholesterol and lipid metabolism, and dysregulation of bile acid metabolism (and resulting alteration of bile acid pool size and composition) has been suggested as one of contributing causes of diabetes. Additionally there is evidence that bile acid synthesis is regulated by insulin and glucose and reciprocally regulates these agents. Thus insulin was shown to repress the expression of FXR gene suggesting that diabetes may be associated with dysregulation of FXR gene expression, and bile salt stimulated FXR has been shown to induce insulin secretion.
[0007] Bile secretion is also regulated by food intake on multiple levels. On one level, consumption of lipid triggers secretion of the hormone cholecystokinin (CCK) by enteroendocrine I cells in the duodenum. CCK enters the circulation and binds to receptors on the gall bladder, thus promoting contraction of smooth muscle cells of the gall bladder and relaxation of the sphincter of Oddi, leading to the pulsatile secretion of bile into the duodenum.
[0008] Food intake also activates parasympathetic nervous system, which in turn increases bicarbonate secretion and subsequent bile secretion. In addition, sympathetic nervous system appears to affect function of cholangiocytes, the epithelial cells of the bile duct, which in turn control bile flow by regulating the secretion and absorption of bile acid and bicarbonate during their passage between the bile canaliculi.
[0009] Another proposed mechanism of bile flow regulation by autonomous nervous system involves prostaglandins. Stimulating of the sympathetic liver nerves with electrical signal in the perfused rat liver, resulted in reduction bile flow and bile acid secretion by way of al- adrenergic receptors. On the other hand administering prostaglandin FZ ,a systemically resulted in stimulation of bile flow.
[00010] Because bile acid synthesis involves liver-specific enzymes, it was initially thought to occur solely in the liver. However, an alternative or“acidic pathway” was discovered, which utilizes enzymes expressed in an array of extrahepatic tissues such as kidney, immune cells, and the brain.
[00011] Bile acids bind to other proteins in addition to their hormone receptors (e.g. FXR and TGR5) and their transporters. Among these protein targets, the enzyme N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD) generates bioactive lipid amides (e.g. the endogenous cannabinoid anandamide) that play important roles in several physiological pathways including stress and pain responses, appetite, and lifespan.
[00012] In addition, inside the intestine, bile acids are further modified into structurally diverse secondary bile acid species by gut microbiota. Different primary and secondary bile acid species exhibit different capacities to bind and activate FXR, making bile acid composition a crucial factor for determining FXR activity in various tissues.
[00013] Bile salts are believed to be the primary steroid in the brain, and while bile salt metabolism in the liver is well- studied, little is known about it behind the blood-brain barrier. These processes however may be highly significant, since at least one bile acid receptor, TGR5, has been shown to be involved in bile acid mediated signaling in the brain, and may mediate bile acid-induced itch and analgesia associated with cholestasis. Another possible pathway of the bile acids action in central nervous system involves FXR-mediated induction of FGF15/19, which was recently shown to regulate metabolism by acting on the brain.
[00014] The bile acid activity in the brain raises the possibility of cross talk between neurosteroids and bile acids, possibly to alter neurotransmission. Neurosteroids classically act to modulate GABAergic tone, and in fact, the bile acids, ursodeoxycholic acid (UDCA) and chenodeoxy cholic acid (CDCA), have been shown recently to antagonize GABAA receptors, and CDCA was shown to antagonize NMDA receptors. Moreover, given the known relationship between bile acid homeostasis, the sympathetic nervous system, and a-adrenergic modulation, the possiblities exist that control of bile acids may have a central regulatory component and/or central bile acid metabolism may have a peripheral component.
[00015] It has been suggested that dysregulation of bile acids may contribute to CNS disorders, such as Alzheimer’s disease (AD). For example, the defects in lipidation of apolipoprotem E (apoE), the most common genetic risk factor for AD, is correlated with amyloid plaques formation. Moreover, chronic unpredictable mild stress (CUMS) treatment, an animal model of depression, resulted in significant biochjemical changes in the liver, specifically altered expression profile of Pla2gl5, Pnpla6, Baat and Gadl, four key enzymes involved in phospholipid and primary bile acid biosynthesis in liver. Also the levels of
tauroursodeoxy cholic acid (TUDCA), a hydrophilic bile acid that is produced in the liver, were enhanced by CUMS treatment.
[00016] In addition, bile acids were found to exert neuroprotective effects in models of Huntington’s disease. Furthermore, TUDCA, was shown to be an effective treatment of amyotrophic lateral sclerosis.
[00017] Bile salts are implicated as having roles in various additional conditions including autism, diabetes, fibromyalgia, post traumatic stress disorder (PTSD), and others. Moreover, the synthesis and release of bile acids is regulated by autonomic nervous system (ANS), in part as a function of circadian rhythm. As such bile acids may mediate metabolic diseases that result from disruption of circadian regulation.
[00018] Accordingly, there exists a need to develop improved compositions and methods for treating bile acid associated diseases.
SUMMARY OF THE INVENTION
[00019] In one aspect, the invention relates to a method for treating a bile acid associated disease or disorder in a subject in need thereof, the method comprising: administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said bile acid associated disease or disorder in said subject. In an exemplary embodiment, said tyrosine hydroxylase inhibitor is racemic a-methyl-DL-tyrosine.
[00020] In another aspect, the invention relates to a composition comprising a tyrosine hydroxylase inhibitor, wherein said tyrosine hydroxylase inhibitor is present in an amount effective to treat a bile acid associated disease or disorder in a subject.
[00021] In yet another aspect, the invention relates to a method for treating a bile acid associated disease or disorder in a subject in need thereof, the method comprising: administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor in combination with another treating agent (e.g., another agent that treats bile acid associated disease or disorder), thereby treating said bile acid associated disease or disorder in said subject.
[00022] In a further aspect, the invention relates to a composition comprising a tyrosine hydroxylase inhibitor in combination with another treating agent, wherein said tyrosine hydroxylase inhibitor and said another treating agent are present in an amount effective to treat a bile acid associated disease or disorder in a subject.
[00023] In an additional aspect, the invention relates to a method of treating a bile acid- associated pathological cognitive condition in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said pathological cognitive condition.
[00024] In yet additional aspect, the invention relates to a method of treating a bile acid- associated neurodegenerative disorder in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said neurodegenerative disorder.
[00025] In yet additional aspect, the invention relates to a method of treating bile acid- associated neuronal damage, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said neuronal damage.
[00026] In yet additional aspect, the invention relates to a method of treating a bile acid- associated diabetes in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating a said diabetes.
[00027] In yet additional aspect, the invention relates to a method of treating a bile acid- associated central nervous system (CNS) disease or disorder, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said CNS disease or disorder.
[00028] In yet additional aspect, the invention relates to a method of treating a disease or disorder associated with bile acid-mediated lipid metabolism, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said disease or disorder.
[00029] Other features and advantages of the present invention will become apparent from the following detailed description examples and figures. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and
modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DFTATFFD DESCRIPTION OF THE INVENTION
[00030] The present subject matter may be understood more readily by reference to the following detailed description which forms a part of this disclosure. It is to be understood that this invention is not limited to the specific products, methods, conditions, or parameters described and/or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed invention.
[00031] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
[00032] As employed above and throughout the disclosure, the following terms and abbreviations, unless otherwise indicated, shall be understood to have the following meanings.
[00033] In the present disclosure the singular forms "a," "an," and "the" include the plural reference, and reference to a particular numerical value includes at least that particular value, unless the context clearly indicates otherwise. Thus, for example, a reference to "a compound" is a reference to one or more of such compounds and equivalents thereof known to those skilled in the art, and so forth. The term "plurality", as used herein, means more than one. When a range of values is expressed, another embodiment incudes from the one particular and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it is understood that the particular value forms another embodiment. All ranges are inclusive and combinable.
[00034] As used herein, the terms "component," "composition," "composition of compounds," "compound," "drug," "pharmacologically active agent," "active agent," "therapeutic," "therapy," "treatment," or "medicament" are used interchangeably herein to refer to a compound or compounds or composition of matter which, when administered to a subject (human or animal) induces a desired pharmacological and/or physiologic effect by local and/or systemic action.
[00035] As used herein, the terms "treatment" or "therapy" (as well as different forms thereol) include preventative (e.g., prophylactic), curative or palliative treatment. As used herein, the term "treating" includes alleviating or reducing at least one adverse or negative effect or symptom of a condition, disease or disorder. This condition, disease or disorder can be acne or its related skin condition.
[00036] The term "stereoisomers" refers to compounds that have identical chemical constitution, but differ as regards the arrangement of the atoms or groups in space. The term "enantiomers" refers to stereoisomers that are mirror images of each other that are non- superimposable.
[00037] The terms "subject," "individual," and "patient" are used interchangeably herein, and refer to an animal, for example a human, to whom treatment, including prophylactic treatment, with the pharmaceutical composition according to the present invention, is provided. The term "subject" as used herein refers to human and non-human animals.
[00038] The term "inhibitor" as used herein includes compounds that inhibit the expression or activity of a protein, polypeptide or enzyme and does not necessarily mean complete inhibition of expression and/or activity. Rather, the inhibition includes inhibition of the expression and/or activity of a protein, polypeptide or enzyme to an extent, and for a time, sufficient to produce the desired effect.
[00039] In some embodiments, provided herein is a method of treatment of bile acid- associated disease or disorder in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
[00040] While not intending to be bound by any particular mechanism of operation, tyrosine hydroxylase inhibitors function by decreasing the functional amount of catecholamine neurotransmitters, including adrenaline, secreted into the bloodstream. Catecholamine neurotransmitters activate sympathetic nervous system, and its improper activation in turn results in excessive bile production and secretion. In this way, bile acids are under the control of the autonomic nervous system and the balance sympathetic and parasympathetic afferent neurotransmission. Thus tyrosine hydroxylase treatment works to suppress sympathetic nervous system signaling and prevent or reverse excessive bile production and secretion, and the inhibition of tyrosine hydroxylase activity can serve to adjust the balance between the arms of the autonomic nervous system.
[00041] In some embodiments, provided herein is a method of altering bile acids metabolism in a subject, the method comprising prevention of activation of sympathetic nervous system activation in said subject, through administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
[00042] Excessive bile production and secretion described above leads to multiple pathologies, including, without limitation, central nervous system disorders, peripheral nervous system disorders, and metabolic disorders. Elevated bile acids levels results in suppression of GABA and NMDA receptor signaling (by bile acids ursodeoxycholic acid (UDCA) and chenodeoxy cholic acid (CDCA)). Thus, the modulation of tyrosine hydroxylase may work to restore GABA and NMDA receptor signaling, thereby preventing or suppressing development of a cognitive condition, such as Alzheimer's disease, autism or PTSD. Excessive bile acids also disrupt blood brain barrier and enter the brain, ultimately causing brain damage and subsequent neurological decline. Tyrosine hydroxylase treatment may work to restore normal levels of bile production and bile acid concentration in serum, thereby preventing neuronal damage.
[00043] FXR activation also induces proliferator-activated receptors (PPARs), which, inter alia, modulate triglyceride (TG) production. Dysregulation of PPARs have been shown to cause behavioral phenotype of cognitive inflexibility, perseveration, blunted responses to psychomimetic drugs, as well as development of other autism- like symptoms in animal models. Thus tyrosine hydroxylase treatment may work to restore normal levels of FXR and PPAR- a, thereby restoring normal neurological function.
[00044] In some embodiments, provided herein is a method of treating a bile acid- associated pathological cognitive condition or a neurodegenerative condition in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
[00045] The present invention further provides for a method of treating a bile acid- associated neuronal damage, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
[00046] In some embodiments, provided herein is a method of treating a bile acid- associated central nervous system (CNS) disease or disorder, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
[00047] In addition, excessive bile production and secretion, activates FXR and CYP7A1. Activation of FXR induces a number of gluconeogenic genes, including phosphoenolpyruvate carboxykinase (PEPCK), one of the rate-controlling enzymes of gluconeogenesis, ultimately leading to excessive levels of liver glucose. Moreover, FXR activation inhibits the induction of glucose-responsive genes, such as L-type pyruvate kinase (L-PK), resulting in reduced glucose sensitivity. Thus tyrosine hydroxylase treatment may work to restore normal levels of FXR, PEPCK and L-PK activity, thereby lowering glucose levels and restoring normal glucose metabolism.
[00048] In one embodiment, provided herein is a method of treating of a bile acid associated metabolic syndrome (e.g., hyperglycemia) in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor. In another embodiment, provided herein is a method of treating of diabetes in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor that influences bile acid release and subsequent orphan receptor function resulting in an increase in insulin sensitivity.
[00049] In some embodiments, provided herein is a method of treating a disease or disorder associated with bile acid-mediated lipid metabolism, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor.
[00050] The tyrosine hydroxylase inhibitor is well known in the art and fully described in, for example, U.S. Patent Application Publications US 2015/0290279, US 2015/0216827, US 2015/0111937, US 2015/0111878, US 2013/0184214, and US 20130183263; U.S. Patents US 8,481,498, US 9,308,188, and US 9,326,962; and PCT Patent Application Publication WO2015061328, which are incorporated by reference herein in their entirety. Any suitable tyrosine hydroxylase inhibitor, known to one of skilled in the art, can be used.
[00051] In certain embodiments, the tyrosine hydroxylase inhibitor is a tyrosine derivative. The tyrosine derivative can be capable of existing in different isomeric forms, including stereoisomers and enantiomers. The tyrosine derivative can, for example, exist in both L-form or D-form. The tyrosine derivative can, for example, also exist in a racemic form.
[00052] Representative tyrosine derivatives include, for example, one or more of methyl (2R)-2-amino-3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2- amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate H-D-tyrosine(tBu)-
allyl ester hydrochloride, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2- amino-3-(4-[(2-chloro-6-fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino- 3-(2-chloro-3,4-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4- hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl) oxy] benzyl malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-amino-3- (2,6- dichloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-4- hy dr oxy phenyl) propanoate, H-DL-tyrosine methyl ester hydrochloride, H-3,5-diiodo-tyrosine methyl ester hydrochloride, H-D-3,5-diiodo-tyrosine methyl ester hydrochloride, H-D-tyrosine methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, D-tyrosine-methyl ester hydrochloride, methyl D-tyrosinate hydrochloride, H-D-tyrosine methyl ester hydrochloride, D-tyrosine methyl ester hydrochloride, H-D-tyrosine methyl ester-hydrochloride, (2R)-2- amino-3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl (2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride, 3-chloro-L-tyrosine, 3-nitro-L- tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL-m-tyrosine, DL-o-tyrosine, Boc- tyrosine (3,5-I2)-OSu, Fmoc-tyrosine(3-N02)-OH, a-methyl-L-tyrosine, a-methyl-D-tyrosine, and a-methyl-DL-tyrosine. In certain embodiments of the invention, the tyrosine derivative is a-methyl-L-tyrosine as shown below:
[00053] In other embodiments, the tyrosine derivative is a-methyl-D-tyrosine. In other embodiments, the tyrosine derivative is a-methyl-DL-tyrosine in a racemic form as shown below:
[00054] In a particular embodiment, the tyrosine derivative is a structural variant of a- methyl-L-tyrosine or a-methyl-DL-tyrosine. The structural variants of a-methyl-L-tyrosine or a-methyl-DL-tyrosine are well known in the art and fully described in, for example, U. S. Patent 4, 160,835, which is incorporated by reference herein in its entirety.
[00055] In one embodiment, the tyrosine derivative of the invention is an arylalanine compound having the formula:
[00056] wherein Ri is hydrogen, methyl or ethyl ester group, or alkyl of from 1 to 4 carbon atoms; R2 is hydrogen, lower alkyl, lower alkene, succinimide, or alkyl of from 1 to 4 carbon atoms; R3 is a substituted benzene ring of the following general formula
wherein Y 1, is located at the para position and is hydrogen, hydroxy, methyl ether, dimethyl ether, trimethyl ether, or an unsubstituted or halogen-substituted benzyl; Y2, and Y3 are the same or different and wherein one or both Y2, and Y3 located at either meta position or ortho position, and wherein Y2, and Y3 are hydrogen, hydroxy, halogen, methyl ether, or nitro; and R4 is hydrogen, acetyl, tert-butyloxycarbonyl or fluorenylmethyloxy carbonyl.
[00057] In some embodiments, Y1 and Y2 are the same or different and are selected from hydrogen, cyanoamino, carboxyl, cyano, thiocarbamoyl, aminomethyl, guanidino, hydroxy, methanesulfonamido, nitro, amino, methanesulfonyloxy, carboxymethoxy, formyl, methoxy and a substituted or unsubstituted 5- or 6-membered heterocyclic ring containing carbon and one or more nitrogen, sulfur or oxygen atoms, specific examples of such heterocyclic rings being pyrrol-l-yl, 2-carboxypyrrol-l-yl, imidazol-2-ylamino, indol-l-yl, carbazol-9-yl, 4,5-dihydro-4-hydroxy-4-trifluoromethylthiazol-3-yl, 4-trifluoromethylthiazol- 2-yl, imidazol-2-yl and 4,5-dihydroimidazol-2-yl, such that (a) Y1 and Y2 cannot both be
hydroxy, (b) Y1 and Y2 cannot both be hydrogen and (c) when one of Y1 and Y2 is hydrogen, the other cannot be hydroxyl.
[00058] In one example, R3 is a substituted or unsubstituted benzoheterocyclic ring having the formula:
in which the benzoheterocyclic ring is selected from the group consisting of indolin-5-yl, 1- (N-benzoylcarbamimidoyl)-indolin-5-yl, l-carbamimidoylindolin-5-yl, 1 H-2-oxindol-5-yl, indol-5-yl, 2-mercaptobenzimidazol-5(6)-yl, 2-aminobenzimidazol-5(6)-yl, 2- methanesulfonamido-benzimidazol-5(6)-yl, 1 H-benzoxazol-2-on-6-yl, 2-aminobenzothiazol- 6-yl, 2-amino-4-mercaptobenzothiazol-6-yl, 2,l,3-benzothiadiazol-5-yl, l,3-dihydro-2,2- dioxo-2,l,3-benzothiadiazol-5-yl, l,3-dihydro-l,3-dimethyl-2,2-dioxo-2,l,3-benzothiadiazol- 5-yl, 4-methyl-2(l H)-oxoquinolin-6-yl, quinoxalin-6-yl, 2-hydroxquinoxalin-6-yl, 2- hydroxyquinoxalin-7-yl, 2,3-dihydroxyquinoxalin-6-yl and 2,3-dihydro-3(4 H)-oxo-l,4- benzoxazin-7-yl.
[00059] In another example, R3 is a substituted or unsubstituted heterocyclic ring having the formula:
[00060] in which the heterocyclic ring is selected from the group consisting of 5- hydroxy-4 H-pyran-4-on-2-yl, 2-hydroxypyrid-4-yl, 2-aminopyrid-4-yl, 2-carboxypyrid-4-yl, or tetrazolo[l,5-a]pyrid-7-yl.
[00061] In one particular embodiment, the tyrosine hydroxylase inhibitor is aquayamycin. In one example, aquayamycin is a compound of the formula set forth below.
[00062] In another particular embodiment, the tyrosine hydroxylase inhibitor is oudenone. In one example, oudenone is a compound of the formula set forth below.
[00064] Other suitable tyrosine hydroxylase inhibitor, known to one of skilled in the art, can also be used. Example of other tyrosine hydroxylase inhibitor include, for example, but not limited to, cycloheximide, anisomycin, 3-iodo-L-tyrosine, pyratrione, phenyl carbonyl derivatives having catechol or triphenolic ring systems, for example, phenethylamine and gallic acid derivatives, 4-isopropyltropolone, 2-(4 -thiazolyl)benzimidazole, 8-hydroxyquinoline, o- phenantroline, 5-iodo-8-hydroxyquinoline, bilirubin, 2,9-dimethyl- 1, 10- phenantroline, a-a’- dipyridil, dibenzo [/./tlquinoxaline. 2.4.6-tripyridil-v-triazine. ethyl 3-amino4H-pyrrolo- isoxazole-5(6H)- carboxylate, a-nitroso- -naphthol, sodium diethyldithiocarbamate, ethylenediamineteraacetic acid (See R Hochster, Metabolic Inhibitors V4: A Comprehensive Treatise 52 Elsevier (2012)).
[00065] In another aspect, the invention relates administering a therapeutically effective amount of another agent useful in the treatment of a bile acid associated disease or disorder. Examples of such another agent useful in the treatment of a bile acid associated disease or disorder include, for example, but not limited to, an agent for treating a bile acid synthesis
disorder, a bile acid sequestrant, a bile acid binding agent, and an agent for treating bile acid reflux. Examples of an agent for treating a bile acid synthesis disorder include, but not limited to, Cholbam (cholic acid), which treats a rare bile acid synthesis disorder. Examples of a bile acid sequestrant include, but not limited to, cholestyramine (Questran, Prevalite), colestipol (Colestid, Flavored Colestid), and colesevelam (Welchol), and medications for lowering LDL cholesterol in conjunction with diet modification. Examples of a bile acid binding agent include, but not limited to, cholestyramine (such as Prevalite) and colestipol. Examples of an agent that treats bile acid reflux include, but not limited to, ursodeoxycholic acid which helps promote bile flow; bile acid sequestrants; and proton pump inhibitors, which block acid production. Additional examples of such another agent useful in the treatment of a bile acid associated disease or disorder include, for example, but not limited to, steroidal or nonsteroidal agonists of FXR and TGR5. The semi-synthetic bile acid obeticholic acid (6-ethyl-CDCA, INT-747) and non-steroidal compounds PX-102 and WAY-362450 are examples for FXR agonists.
[00066] The invention also provides a pharmaceutical composition comprising compounds of the invention and one or more pharmaceutically acceptable carriers. “Pharmaceutically acceptable carriers” include any excipient which is nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. The pharmaceutical composition may include one or additional therapeutic agents.
[00067] "Pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
[00068] Pharmaceutically acceptable carriers include solvents, dispersion media, buffers, coatings, antibacterial and antifungal agents, wetting agents, preservatives, buggers, chelating agents, antioxidants, isotonic agents and absorption delaying agents.
[00069] Pharmaceutically acceptable carriers include water; saline; phosphate buffered saline; dextrose; glycerol; alcohols such as ethanol and isopropanol; phosphate, citrate and other organic acids; ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose,
mannose, or dextrins; EDTA; salt forming counterions such as sodium; and/or nonionic surfactants such as TWEEN, polyethylene glycol (PEG), and PLURONICS; isotonic agents such as sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride; as well as combinations thereof.
[00070] Within the present invention, the disclosed compounds may be prepared in the form of pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. These physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.
[00071] Compounds described herein can be prepared in alternate forms. For example, many amino-containing compounds can be used or prepared as an acid addition salt. Often such salts improve isolation and handling properties of the compound. For example, depending on the reagents, reaction conditions and the like, compounds as described herein can be used or prepared, for example, as their hydrochloride or tosylate salts. Isomorphic crystalline forms, all chiral and racemic forms, N-oxide, hydrates, solvates, and acid salt hydrates, are also contemplated to be within the scope of the present invention.
[00072] Certain acidic or basic compounds of the present invention may exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated to be within the scope of the present invention. It is well known in the art that compounds containing both amino and carboxy groups often exist in equilibrium with their
zwitterionic forms. Thus, any of the compounds described herein that contain, for example, both amino and carboxy groups, also include reference to their corresponding zwitterions.
[00073] The pharmaceutical compositions of the invention may be formulated in a variety of ways, including for example, solid, semi-solid, and liquid dosage forms, such as tablets, pills, powders, liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, liposomes and suppositories. In some embodiments, the compositions are in the form of injectable or infusible solutions. The composition is in a form suitable for oral, topical, intravenous, intraarterial, intramuscular, subcutaneous, parenteral, transmucosal, or transdermal administration. The composition may be formulated as an immediate, controlled, extended or delayed release composition.
[00074] Preparations for administration may also include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media. In the subject invention, pharmaceutically acceptable carriers include, but are not limited to, 0.01-0.1M and preferably 0.05M phosphate buffer or 0.8% saline. Other common parenteral vehicles include sodium phosphate solutions, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers, such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present such as for example, antimicrobials, antioxidants, chelating agents, and inert gases and the like.
[00075] More particularly, pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In such cases, the composition must be sterile and should be fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and will preferably be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Suitable formulations for use in the therapeutic methods disclosed
herein are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., 16th ed. (1980).
[00076] In some embodiments, the composition includes isotonic agents, for example, sugars, polyalcohols, such as mannitol, sorbitol, or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
[00077] Sterile solutions can be prepared by incorporating the molecule, by itself or in combination with other active agents, in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle, which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, one method of preparation is vacuum drying and freeze-drying, which yields a powder of an active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. The preparations for injections are processed, filled into containers such as ampoules, bags, bottles, syringes or vials, and sealed under aseptic conditions according to methods known in the art. Further, the preparations may be packaged and sold in the form of a kit such as those described in US Appl. Publ. No. 2002/0102208 Al, which is incorporated herein by reference in its entirety. Such articles of manufacture will preferably have labels or package inserts indicating that the associated compositions are useful for treating a subject suffering from, or predisposed to autoimmune or neoplastic disorders.
[00078] Effective doses of the compositions of the present invention, for treatment of conditions or diseases as described herein vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, and whether treatment is prophylactic or therapeutic. Usually, the patient is a human but non-human mammals including transgenic mammals can also be treated. Treatment dosages may be titrated using routine methods known to those of skill in the art to optimize safety and efficacy.
[00079] The pharmaceutical compositions of the invention may include a“therapeutically effective amount.” A“therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of a molecule may vary according to factors such as the disease state, age, sex,
and weight of the individual, and the ability of the molecule to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of the molecule are outweighed by the therapeutically beneficial effects.
[00080] In one aspect, the dosage of tyrosine hydroxylase inhibitor may range from about 1 mg to about 4g. In a particular embodiment, the dosage of tyrosine hydroxylase inhibitor may range from about 3 mg to about 1000 mg. In some suitable embodiments of the invention, 25 mg of the tyrosine hydroxylase inhibitor is administered. In one example, 60 mg of the tyrosine derivative can be administered orally. In another example, 0.25 mL of a 2 mg/mL suspension of the tyrosine derivative can be administered subcutaneously.
[00081] In another aspect, the dosage of another agent useful in the treatment of a bile acid associated disease or disorder may include a therapeutically effective or clinically acceptable amount. In another example, the dosage of another agent is an amount that complements with or enhances the effect of a tyrosine hydroxylase inhibitor described herein.
[00082] As used herein, the terms“treat” and“treatment” refer to therapeutic treatment, including prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change associated with a disease or condition. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of the extent of a disease or condition, stabilization of a disease or condition (i.e., where the disease or condition does not worsen), delay or slowing of the progression of a disease or condition, amelioration or palliation of the disease or condition, and remission (whether partial or total) of the disease or condition, whether detectable or undetectable. Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition or those in which the disease or condition is to be prevented.
[00083] The diseases or disorders treated by the composition of the invention include, for example, a bile acid associated disease or disorder. Examples of a bile acid associated disease or disorder include, for example, but not limited to, stress; glucose metabolism disorders, such as insulin sensitivity, hyperglycemia, hypertriglyceridemia, diabetes, obesity & related events , for example coronary disease and atherosclerosis; central nervous system disorders, such as amyotrophic lateral sclerosis, encephalopathy, Alzheimer’s Disease, Huntington’s disease, autism, sensory transduction, neuromyelitis optica, depression, cerebrotendinous xanthomatosis, fibromyalgia, post traumatic stress disorder (PTSD), and dementia; psychotic disorders, for example, bipolar disorder and schizophrenia; lipid metabolism disorders, for example,
hyperlipidemia, dyslipidemia, hypercholesterolemia, fatty liver disease; and multiple additional disorders, such as gallstones, colon cancer, inflammatory bowel disease, liver fibrosis, alcoholic liver disease, hypertension, acute pancreatitis, Dubin-Johnson syndrome, sclerosing cholangitis, Crohn’s disease, irritable bowel syndrome, ulcerative colitis, liver cirrhosis, sleep apnea, hepatocellular carcinoma, bile acid reflux, acne, leaky gut syndrome, and others.
[00084] In one aspect, the invention provides administering to a subject a therapeutically effective amount of a first tyrosine hydroxylase inhibitor, for example, a-methyl-DL-tyrosine in combination with a therapeutically effective amount of a second tyrosine hydroxylase inhibitor, for example, a-methyl-L-tyrosine. In another aspect, the invention provides administering to a subject a therapeutically effective amount of one or more tyrosine hydroxylase inhibitors, for example, a-methyl-DL-tyrosine and/or a-methyl-L-tyrosine in combination with a therapeutically effective amount of another agent useful in the treatment of a bile acid associated disease or disorder.
[00085] In another aspect, the invention provides a composition comprises a tyrosine hydroxylase inhibitor, wherein said tyrosine hydroxylase inhibitor is present in an amount effective to treat a bile acid associated disease or disorder in a subject. In an exemplary embodiment, the tyrosine hydroxylase inhibitor is a-methyl-DL-tyrosine. In one embodiment, the composition further comprises a therapeutically effective amount of another tyrosine hydroxylase inhibitor, for example, metyrosine or a-methyl-L-tyrosine. In yet another embodiment, the composition further comprises a therapeutically effective amount of another agent, known to one of skilled in the art, useful in the treatment of a bile acid associated disease or disorder.
[00086] In some embodiments, a tyrosine hydroxylase inhibitor or a composition described above can be administered with another treating agent (e.g., another agent that treats a bile acid associated disease or disorder), known in the art, for example, but not limited to, an agent for treating a bile acid synthesis disorder, a bile acid sequestrant, a bile acid binding agent, and an agent for treating bile acid reflux.
[00087] In one embodiment, a tyrosine hydroxylase inhibitor or a composition described above can be administered in combination with another treatment procedure, known to one of skilled in the art.
[00088] Administration of the tyrosine hydroxylase inhibitor or the tyrosine hydroxylase inhibitor and the another agent can be through various routes, including orally, topically, subcutaneously, intravenously, intramuscularly, transdermally, or in any combination thereof.
[00089] In one embodiment, tyrosine hydroxylase inhibitor is co-administered with another treating agent. In another embodiment, tyrosine hydroxylase inhibitor is administered independently from the administration of another treating agent. In one embodiment, tyrosine hydroxylase inhibitor is administered first, followed by the administration of another treating agent. In another embodiment, said another treating agent is administered first, followed by the administration of said tyrosine hydroxylase inhibitor. In another embodiment a tyrosine hydroxylase can be combined with an agent which stimulates endogenous bile acid release such as estradiol.
[00090] The administration of the tyrosine hydroxylase inhibitor with another treating agent and/or other treatments may occur simultaneously, or separately, via the same or different route, at the same or different times. Dosage regimens may be adjusted to provide the optimum desired response (e.g., a therapeutic or prophylactic response).
[00091] In one example, a single bolus may be administered. In another example, several divided doses may be administered over time. In yet another example, a dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. Dosage unit form, as used herein, refers to physically discrete units suited as unitary dosages for treating mammalian subjects. Each unit may contain a predetermined quantity of active compound calculated to produce a desired therapeutic effect. In some embodiments, the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic or prophylactic effect to be achieved.
[00092] The composition of the invention may be administered only once, or it may be administered multiple times. For multiple dosages, the composition may be, for example, administered three times a day, twice a day, once a day, once every two days, twice a week, weekly, once every two weeks, or monthly.
[00093] It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the
compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
[00094] “Administration" to a subject is not limited to any particular delivery system and may include, without limitation, oral (for example, in capsules, suspensions or tablets), parenteral (including subcutaneous, intravenous, intramedullary, intraarticular, intramuscular, or intraperitoneal injection), topical, or transdermal. Administration to a host may occur in a single dose or in repeat administrations, and in any of a variety of physiologically acceptable salt forms, and/or with an acceptable pharmaceutical carrier and/or additive as part of a pharmaceutical composition (described earlier). Once again, physiologically acceptable salt forms and standard pharmaceutical formulation techniques are well known to persons skilled in the art (see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co.).
[00095] The composition of the invention may be administered topically or orally. The composition of the invention may also be administered parenterally (e.g., intravenous, subcutaneous, intraperitoneal, intramuscular). Further, the composition of the invention may be administered by intravenous infusion or injection. The composition of the invention may be administered by intramuscular or subcutaneous injection. In some embodiments, the composition of the invention may be administered by any suitable route known to one of skilled in the art. As used herein, a "composition" refers to any composition that contains a pharmaceutically effective amount of one or more active ingredients (e.g., a tyrosine hydroxylase inhibitor, another acne treating agent, or a combination thereol).
[00096] In another aspect, provided herein is a method for diagnosing a bile acid associated disease or disorder in a subject, said method comprising: obtaining a biological sample from said subject; determining the presence or absence of a polymorphism in cytochrome P450 3A4 (CYP3A4) in said sample, wherein the presence of said polymorphism in said sample indicates the presence of said disease in said subject. In another aspect, the invention relates to treating a bile acid associated disease or disorder based on the determination of the polymorphism in CYP3A4.
[00097] Cytochrome P450 3A4 (CYP3A4), is a member of cytochrome 450 superfamily of monooxygenase enzymes and is mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. This enzyme is involved in the metabolism of approximately half the
drugs in use today, including acetaminophen, codeine, cyclosporin A, diazepam and erythromycin. The enzyme also metabolizes some steroids and carcinogens.
[00098] Although CYP3A4 is predominantly found in the liver, it is also present in other organs and tissues of the body, where it may play an important role in metabolism. In the intestine, CYP3A4, CYP2B, CYP2C, and epimerases are involved in detoxification of LCA to more soluble hyocholic acid and ursodeoxycholic acid (UDCA) in humans. CYP3A4 also possesses epoxygenase activity in that it metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs). Recently CYP3A4 has also been identified in the brain, however its role in the central nervous system is still unknown.
[00099] CYP3A4 is induced by a wide variety of ligands. These ligands bind to the pregnane X receptor (PXR). The activated PXR complex forms a heterodimer with the retinoid X receptor (RXR), which binds to the XREM region of the CYP3A4 gene. In addition, CYP3A4 availability is mediated by bile acids (via a feedback regulatory loop operating through VDR-mediated signaling), certain corticosteroids, vitamin D, androstane, estrogens, as well as multiple other endogenous compounds and xenobiotics. Finally its levels are subject to circadian cycle.
[000100] The polymorphism in CYP3A4 can be any type of polymorphism, known to one of skilled in the art. In a particular embodiment, the polymorphism is a single-nucleotide polymorphism (SNP), known to one of skilled in the art.
[000101] A single-nucleotide polymorphism (SNP) is a variation in a single nucleotide that occurs at a specific position in the genome, where each variation is present to some appreciable degree within a population. While rarely altering function of proteins encoded by the genes where SNPs occur, they are known to associate with various phenotypic traits, including diseases such as cancer. Genetic association studies of SNPs have identified numerous examples of association between SNPs and different pathologies. This makes SNPs a potentially valuable diagnostic tool, and discovery of novel SNP-pathology association a promising area of research. The methods of SNP detection are well known in the art and include dynamic allele-specific hybridization, use of molecular beacons and SNP microarrays, restriction fragment length polymorphism analysis, PCR-based analysis, FLAP endonuclease assays, primer extension assays, 5’- nuclease assay, oligonucleotide ligation assay, single strand conformation polymorphism assay, temperature gradient gel electrophoresis, high
resolution melting analysis, use of DNA mismatch-binding proteins, surveyor nuclease assay, high throughput sequencing, among others.
[000102] While over 28 single nucleotide polymorphisms (SNPs) have been identified in the CYP3A4 gene. CYP3A4 alleles which have been reported to have minimal function compared to wild-type include CYP3A4*6 (an A17776 insertion) and CYP3A4*17 (F189S). Both of these SNPs led to decreased catalytic activity with certain ligands, including testosterone and nifedipine in comparison to wild-type metabolism.
[000103] The polymorphism in CYP3A4 can be detected by any suitable method known to one of skilled in the art, for example, but not limited to, a polymerase chain reaction (PCR) based method, a microarray based method, a sothem blotting, a western blotting, an in situ hybridisation, and other methods known in the art.
[000104] The term“subject,” as used herein, may refer to any suitable mammal, including primates, such as monkeys and humans, horses, cows, cats, dogs, rabbits, and rodents such as rats and mice. In a partucular embodiment, the subject is a human subject.
[000105] All patents and literature references cited in the present specification are hereby incorporated by reference in their entirety.
[000106] The following examples are provided to supplement the prior disclosure and to provide a better understanding of the subject matter described herein. These examples should not be considered to limit the described subject matter. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be apparent to persons skilled in the art and are to be included within, and can be made without departing from, the true scope of the invention.
EXAMPLES
EXAMPLE 1
Treating bile acid associated disorder
[000107] The composition having a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL tyrosine) can be orally administered to a patient three times a day for five days at individual doses between 50-1500 mg.
[000108] The composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles. The symptoms can be monitored for all subjects biweekly.
[000109] Misalignment of sympathetic and parasympathetic nervous systems can be adjusted with the composition of the invention.
[000110] Overall, the above-noted treatment can be well tolerated by the patient, and responses can be documented for the treatment.
EXAMPLE 2
Treating bile acid associated autism
[000111] The composition having a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL tyrosine) can be orally administered to a patient three times a day at individual doses between 50-1500 mg.
[000112] The assessment can include social initiations, play, gestures, requests, eye contact, joint attention, etc. pressed for, observed, and coded by examiner. Using ADOS, an examiner pulls for target behaviors through specific use of toys, activities, and interview questions; and stereotypical behaviors, sensory sensitivities, aberrant behaviors and the like are also observed and coded. Autism Diagnostic Observational Schedule (ADOS) typically requires about 30-60 minutes of observation, followed by about 15 minutes of scoring; utilizes 29 questions, of which 12-14 are used for scoring; and requires about 60-90 minutes for total assessment. For example, the Autism Diagnostic Observational Schedule-Generic (ADOS-G) exam is divided into four modules. Each of the modules is geared towards a specific group of individuals based on their level of language and to ensure coverage for wide variety of behavioral manifestations. Module 1, containing 10 activities and 29 items, is focused on individuals with little or no language and therefore most typical for assessment of younger children.
[000113]Non-psychogenic assessments of autistim related symptoms such as effects on digestion, elimination, sleep, or other manifestations of autism can be assessed.
[000114] Overall, the above-noted treatment can be well tolerated by the patient, and responses can be documented for the treatment.
EXAMPLE 3
Treating bile acid associated diabetes
[000115] The composition having a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL tyrosine) can be orally administered to a patient in single or divided doses between 50-1500 mg.
[000116] The composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles. The diabetes symptoms, such as blood glucose levels, can be monitored for all subjects biweekly through fasting plasma glucose (FPG) test, the AIC test, or random plasma glucose (RPG) test.
[000117] Overall, the above-noted treatment can be well tolerated by the patient, and responses can be documented for the treatment.
EXAMPLE 4
Treating bile acid associated PTSD
[000118] The composition having a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL tyrosine) can be orally administered to a patient in single or divided doses between 50-1500 mg.
[000119] The composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles. The PTSD symptoms can be monitored for all subjects biweekly through, for example evaluation under Structured Interview for PTSD (SI-PTSD; Davidson et al, J Nervous Mental Disease 177:336-41 (1989)), the Clinician Administered PTSD Scale (CAPS; Blake et al, Behavior Therapist 13: 187-8 (1990)) or the Short Screening Scale for DSM-IV PTSD (Breslau et al, Am J Psychiatry 156:908-11 (1999)).
[000120] Overall, the above-noted treatment can be well tolerated by the patient, and responses can be documented for the treatment.
EXAMPLE 5
Treating schizophrenia
[000121] The composition having a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL tyrosine) can be orally administered to a patient in single or divided doses between 50-1500 mg.
[000122] The composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles. The symptoms can be monitored for all subjects biweekly.
[000123] Overall, the above-noted treatment can be well tolerated by the patient, and responses can be documented for the treatment.
EXAMPLE 6
Treating fibromyalgia
[000124] The composition having a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL tyrosine) can be orally administered to a patient in single or divided doses between 50-1500 mg.
[000125] The composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles. The symptoms can be monitored for all subjects biweekly.
[000126] Overall, the above-noted treatment can be well tolerated by the patient, and responses can be documented for the treatment.
EXAMPLE 7
Treating leaky gut syndrome
[000127] The composition having a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL tyrosine) can be orally administered to a patient in single or divided doses between 50-1500 mg.
[000128] The composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles. The symptoms can be monitored for all subjects biweekly.
[000129] Overall, the above-noted treatment can be well tolerated by the patient, and responses can be documented for the treatment.
EXAMPLE 8
Treating liver disease
[000130] The composition having a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL tyrosine) can be orally administered to a patient in single or divided doses between 50-1500 mg.
[000131] The composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles. The symptoms can be monitored for all subjects biweekly.
[000132] Overall, the above-noted treatment can be well tolerated by the patient, and responses can be documented for the treatment.
EXAMPLE 9
Treating sleep apnea
[000133] The composition having a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL tyrosine) can be orally administered to a patient in single or divided doses between 50-1500 mg.
[000134] The composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles. The symptoms can be monitored for all subjects biweekly.
[000135] Overall, the above-noted treatment can be well tolerated by the patient, and responses can be documented for the treatment.
EXAMPLE 10
Treating acne
[000136] The composition having a tyrosine hydroxylase inhibitor (e.g., a-methyl-DL tyrosine) can be orally administered to a patient in single or divided doses between 50-1500 mg.
[000137] The composition of the invention can be administered periodically, for example, each of five days per week for a period of six weeks, with one or two days off between weekly cycles. The symptoms can be monitored for all subjects biweekly.
[000138] Overall, the above-noted treatment can be well tolerated by the patient, and responses can be documented for the treatment.
[000139] Having described preferred embodiments of the invention, it is to be understood that the invention is not limited to the precise embodiments, and that various changes and modifications may be effected therein by those skilled in the art without departing from the scope or spirit of the invention as defined in the appended claims.
Claims
1. A method for treating a bile acid associated disease or disorder in a subject in need thereof, the method comprising: administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said bile acid associated disease or disorder in said subject.
2. The method of claim 1, wherein said tyrosine hydroxylase inhibitor is racemic a- methyl-DL-tyrosine.
3. The method of claim 1, wherein said tyrosine hydroxylase inhibitor is metyrosine or a- methyl-L-tyrosine.
4. The method of claim 1, wherein said tyrosine hydroxylase inhibitor is a-methyl-D- tyrosine.
5. The method of claim 1, wherein said tyrosine hydroxylase inhibitor is a tyrosine derivative.
6. The method of claim 5, wherein said tyrosine derivative is methyl (2R)-2-amino-3-(2- chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)-2- amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate H-D-Tyr(TBU)-allyl ester HC1, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3- (2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4-[(2-chloro-6- fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino-3-(2-chloro-3,4- dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl) oxy] benzyl malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3- chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2,6- dichloro-3- hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3 -(3 -chi oro-4-hydroxy phenyl) propanoate, H-DL-tyr-OME HC1, H-3,5-diiodo-tyr-OME HC1, H-D-3,5-diiodo-tyr-OME HC1, H-D-tyr-OME HC1, D-tyrosine methyl ester hydrochloride, D-tyrosine-ome HC1, methyl D- tyrosinate hydrochloride, H-D-tyr-OMe HCl, D-tyrosine methyl ester HC1, H-D-Tyr-OMe- HC1, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl (2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride, 3-
chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride,
tyrosine, DL-o-tyrosine, Boc-Tyr (3,5-l2)-OSu, Fmoc-tyr(3-N02)-OH, a-methyl-L-tyrosine, a- methyl-D-tyrosine, a-methyl-DL-tyrosine, or a combination thereof.
7. The method of claim 1, wherein 100-1500 mg of said tyrosine hydroxylase inhibitor is administered daily.
8. The method of claim 1, wherein said tyrosine hydroxylase inhibitor is administered in one, two, three, or four doses, each day.
9. The method of claim 1, wherein said tyrosine hydroxylase inhibitor is administered orally, subcutaneously, intravenously, topically, transdermally, vaginally, rectally or in any combination thereof.
10. The method of claim 1, wherein said method further comprising administering to said subject an effective amount of another pharmaceutical composition useful in the treatment of a bile acid associated disease or disorder.
11. The method of claim 1 , wherein said another pharmaceutical composition comprises an agent for treating a bile acid synthesis disorder, a bile acid sequestrant, a bile acid binding agent, an agent for treating bile acid reflux, or a combination thereof.
12. The method of claim 11, wherein said another pharmaceutical composition comprises cholic acid, cholestyramine, colestid, colesevelam, a medication for lowering cholesterol, ursodeoxycholic acid, a bile acid sequestrant, a proton pump inhibitor, PPAR-a agonist, PPAR- g agonist, FXR agonist, RXR agonist TGR5 agonist, or a combination thereof.
13. The method of claim 10, wherein said another pharmaceutical composition and said tyrosine hydroxylase inhibitor are administered concurrently or sequentially.
14. The method of claim 1, said bile acid associated disease or disorder is associated with the synthesis or release of bile acids, or the sensitivity of the response to bile acids.
15. A composition comprising a tyrosine hydroxylase inhibitor, wherein said tyrosine hydroxylase inhibitor is present in an amount effective to treat a bile acid associated disease or disorder in a subject.
16. The composition of claim 15, wherein said tyrosine hydroxylase inhibitor is racemic a- methyl-DL-tyrosine.
17. The composition of claim 15, wherein said tyrosine hydroxylase inhibitor is metyrosine or a-methyl-L-tyrosine.
18. The composition of claim 15, wherein said tyrosine hydroxylase inhibitor is a-methyl- D-tyrosine.
19. The composition of claim 15, wherein said tyrosine hydroxylase inhibitor is a tyrosine derivative.
20. The composition of claim 19, wherein said tyrosine derivative is methyl (2R)-2-amino- 3-(2-chloro-4 hydroxyphenyl) propanoate, D-tyrosine ethyl ester hydrochloride, methyl (2R)- 2- amino-3-(2,6-dichloro-3,4-dimethoxyphenyl) propanoate H-D-Tyr(TBU)-allyl ester HC1, methyl (2R)-2-amino-3-(3-chloro-4,5-dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3- (2-chloro-3-hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(4-[(2-chloro-6- fluorophenyl) methoxy] phenyl) propanoate, methyl (2R)-2- amino-3-(2-chloro-3,4- dimethoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3-chloro-5-fluoro-4-hydroxyphenyl) propanoate, diethyl 2-(acetylamino)-2-(4-[(2-chloro-6-fluorobenzyl) oxy] benzyl malonate, methyl (2R)-2-amino-3-(3-chloro-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(3- chloro-4-hydroxy-5-methoxyphenyl) propanoate, methyl (2R)-2-amino-3-(2,6- dichloro-3- hydroxy-4-methoxyphenyl) propanoate, methyl (2R)-2-amino-3 -(3 -chi oro-4-hydroxy phenyl) propanoate, H-DL-tyr-OME HC1, H-3,5-diiodo-tyr-OME HC1, H-D-3,5-diiodo-tyr-OME HC1, H-D-tyr-OME HC1, D-tyrosine methyl ester hydrochloride, D-tyrosine-ome HC1, methyl D- tyrosinate hydrochloride, H-D-tyr-OMe HCl, D-tyrosine methyl ester HC1, H-D-Tyr-OMe- HC1, (2R)-2-amino-3-(4-hydroxyphenyl) propionic acid, (2R)-2-amino-3-(4-hydroxyphenyl) methyl ester hydrochloride, methyl (2R)-2-amino-3-(4-hydroxyphenyl) propanoate hydrochloride, methyl (2R)-2-azanyl-3-(4-hydroxyphenyl) propanoate hydrochloride, 3- chloro-L-tyrosine, 3-nitro-L-tyrosine, 3-nitro-L-tyrosine ethyl ester hydrochloride, DL -m- tyrosine, DL-otyrosine, Boc-Tyr (3,5-l2)-OSu, Fmoc-tyr(3-N02)-OH, a-methyl-L-tyrosine, a- methyl-D-tyrosine, a-methyl-DL-tyrosine, or a combination thereof.
21. The composition of claim 15, wherein said tyrosine hydroxylase inhibitor is present in an amount of 150-500 mg.
22. The composition of claim 15, wherein said composition further comprising an effective amount of another pharmaceutical composition useful in the treatment of a bile acid associated disease or disorder.
23. The composition of claim 22, wherein said another pharmaceutical composition comprises an agent for treating a bile acid synthesis disorder, a bile acid sequestrant, a bile acid binding agent, an agent for treating bile acid reflux, or a combination thereof.
24. The composition of claim 22, wherein said another pharmaceutical composition comprises cholic acid, cholestyramine, colestid, colesevelam, a medication for lowering cholesterol, ursodeoxycholic acid, a bile acid sequestrant, a proton pump inhibitor, FXR agonist PPAR-a agonist, PPAR-g agonist, RXR agonist, and TGR5 agonist.
25. The composition of claim 1, said bile acid associated disease or disorder is associated with the synthesis of bile acid.
26. A method for treating a bile acid associated disease or disorder in a subject in need thereof, the method comprising: administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor in combination with another agent that treats a bile acid associated disease or disorder, thereby treating said bile acid associated disease or disorder in said subject.
27. The method of claim 26, wherein said another treating agent is cholic acid, cholestyramine, colestid, colesevelam, a medication for lowering cholesterol, ursodeoxycholic acid, a bile acid sequestrant, a proton pump inhibitor, FXR agonist, PPAR-a agonist, PPAR-g agonist, RXR agonist, and TGR5 agonist.
28. A composition comprising a tyrosine hydroxylase inhibitor in combination with another treating agent that treats bile acid associated disease or disorder, wherein said tyrosine hydroxylase inhibitor and said another treating agent are present in an amount effective to treat a bile acid associated disease or disorder in a subject.
29. The method of claim 27, wherein said another treating agent is cholic acid, cholestyramine, colestid, colesevelam, a medication for lowering cholesterol, ursodeoxycholic acid, a bile acid sequestrant, a proton pump inhibitor, FXR agonist, PPAR-a agonist, PPAR-g agonist, RXR agonist, and TGR5 agonist.
30. A method for diagnosing a bile acid associated disease or disorder in a subject, said method comprising: obtaining a biological sample from said subject; determining the presence or absence of a polymorphism in cytochrome P450 3A4 (CYP3A4) in said sample, wherein the presence of said polymorphism in said sample indicates the presence of said disease or disorder in said subject, thereby diagnosing said disease or disorder in said subject.
31. A method for treating a bile acid associated disease or disorder in a subj ect, the method comprising: obtaining a biological sample from said subject; determining the presence or absence of a polymorphism in cytochrome P450 3A4 (CYP3A4) in said sample, wherein the presence of said polymorphism in said sample indicates the presence of said disease or disorder in said subject; based on the determination of the polymorphism in CYP3A4, treating said bile acid associated disease or disorder in said subject.
32. A method of treating a bile acid-associated pathological cognitive condition in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said pathological cognitive condition.
33. The method of claim 32, wherein said pathological cognitive condition is Alzheimer’s Disease, PTSD, or an autism spectrum disorder.
34. A method of treating a bile acid-associated neurodegenerative disorder in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said neurodegenerative disorder.
35. The method of claim 34, wherein said neurodegenerative disorder is Parkinson’s Disease, Huntington’s Disease, Fibromyalgia, or, amyotrophic lateral sclerosis.
36. A method of treating bile acid-associated neuronal damage, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said neuronal damage.
37. A method of treating a bile acid-associated central nervous system (CNS) disease or disorder, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said CNS disease or disorder.
38. A method of treating a bile acid-associated metabolic syndrome, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said metabolic syndrome.
39. A method of treating a bile acid-associated diabetes in a subj ect, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said diabetes.
40. A method of treating a bile acid-associated leaky gut syndrome in a subject, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said leaky gut syndrome.
41. A method of treating a disease or disorder associated with bile acid-mediated lipid metabolism, the method comprising administering to said subject a therapeutically effective amount of a tyrosine hydroxylase inhibitor, thereby treating said disease or disorder.
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