WO2019129120A1

WO2019129120A1 - Tolcapone for prevention and/or treatment of obesity and related metabolic diseases

Info

Publication number: WO2019129120A1
Application number: PCT/CN2018/124185
Authority: WO
Inventors: Niu Huang; Shiming PENG; Nannan HOU; Wei Li
Original assignee: Rpxds Co., Ltd
Priority date: 2017-12-28
Filing date: 2018-12-27
Publication date: 2019-07-04
Also published as: CN111902136A

Abstract

Disclosed herein is tolcapone as an FTO inhibitor for use in reducing food intake or appetite, reducing weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, for use in preventing or treating obesity or an obesity related disease (especially diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases), or ameliorating or reducing the pathology or severity of obesity or an obesity related disease or a symptom of obesity or an obesity related disease. Also disclosed here is a pharmaceutical composition comprising tolcapone or a pharmaceutically acceptable salt or a prodrug thereof co-packaged or co-formulated with a second different medicament, e. g., for controlling appetite and/or reducing food intake, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis.

Description

TOLCAPONE FOR PREVENTION AND/OR TREATMENT OF OBESITY AND RELATED METABOLIC DISEASES

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of PCT application No. PCT/CN2017/119443 filed on December 28, 2017, the disclosure of which is hereby incorporated by reference for all purposes.

FILED OF THE INVENTION

Disclosed herein is tolcapone as an FTO inhibitor for use in reducing food intake or appetite, reducing weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, and/or triglycerides, for use in preventing or treating obesity or an obesity related disease (especially diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases) , or ameliorating or reducing the pathology or severity of obesity or an obesity related disease or a symptom of obesity or an obesity related disease. Also disclosed here is a pharmaceutical composition comprising tolcapone or a pharmaceutically acceptable salt or a prodrug thereof co-packaged or co-formulated with a second different medicament, e.g., for reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis.

BACKGROUND OF THE INVENTION

Obesity is a severe health problem worldwide and many factors contribute to this chronic disease, including environmental factors and genetic factors. Genome-wide association studies to investigate patients with obesity revealed a gene for FTO (fat mass and obesity) to strongly associate with obesity. FTO’s functional role in obesity was confirmed in transgenic animal models, such as FTO knockout mouse, FTO-overexpression mouse and FTO-I367F mutation mouse. More specifically, FTO global-knockout and neuron-specific knockout induce body weight loss, while FTO gene overexpression results in obesity. One mis-sense mutation was observed to inhibit FTO enzymatic function and protect mouse from obesity. Nevertheless, FTO is expressed in many tissues, especially in hypothalamic nuclei controlling energy expenditure, which is consistent with the suggestion that FTO affects energy homeostasis.

FTO protein is an α-ketoglutarate and iron (II) dependent nucleic acid demethylase. Its preferred substrate is N ⁶-meA in message RNA, which locates near the stop codon and influences gene translation.

WO2014082544A1 discloses entacapone used as an FTO inhibitor for inhibiting weight gain, wherein the methods are also applicable to promoting weight loss, reducing serum LDL, cholesterol, LDL-c, and/or triglycerides, and/or treating an obesity related or metabolic disease. However, the body-weight-normalized food intakes between the entacapone treated group and the control group showed no difference (see, Fig. 5 and paragraph [0051] of WO2014082544A1) . This was consistent with the discovery of Maarit Hakanen et al. in J Clin Endocrinol Metab. 2009; 94 (4) : 1281-7, which reported that risk allele of FTO SNPs is not directly associated with food intake. To the contrary, overexpression of FTO was reported to lead to increased food intake and result in obesity, see Nature Genetics, published online 14 Nov 2010, doi: 10.1038/ng. 713. Therefore, the effect of FTO function on food intake still remains unclear.

On the other side, the co-pending PCT application PCT/CN2017/119404 filed by the applicant on the same day confirms compounds which may inhibit COMT, but have no inhibition against FTO.

Obesity most commonly arises as a result of the imbalance of caloric intake (eating) vs.caloric expenditure. Regardless of the underlying physiological cause of obesity, appetite regulation is a key factor in controlling weight gain and maintenance of body weight. Therefore, it is necessary to curb or control appetite and/or reduce food intake in patients with obesity or an obesity related disease so as to control body weight and so as to prevent or treat obesity or any of the obesity related diseases.

SUMMARY OF THE INVENTION

Tolcapone is a potent and reversible COMT inhibitor used to treat Parkinson's disease (PD) . The inhibitory activity of tolcapone against COMT was reproduced in Example 5 disclosed herein. Tolcapone has the chemical name of (3, 4-dihydroxy-5-nitrophenyl) (p-tolyl) methanone and the following chemical structure:

Unexpectedly, the inventors of the present invention found that tolcapone as an FTO inhibitor exhibited a significant reduction in appetite (or food intake, interchangeably disclosed herein) leading to reductions in body weight in a subject, in addition to reduction of weight gain, promotion of weight loss, reduction of blood glucose, reduction of serum LDL, cholesterol, LDL-c, or triglycerides (especially significant reduction of blood glucose) , or prevention or treatment of obesity or an obesity related disease.

In the first aspect, disclosed herein is a method for controlling appetite and/or reducing food intake in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of tolcapone or a pharmaceutically acceptable salt or a prodrug thereof.

In the second aspect, disclosed herein is a method for reducing weight gain and/or promoting weight loss in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of tolcapone or a pharmaceutically acceptable salt or a prodrug thereof.

In the third aspect, disclosed herein is a method for reducing of blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of tolcapone or a pharmaceutically acceptable salt or a prodrug thereof.

In the fourth aspect, disclosed herein is a method for use in preventing or treating obesity or an obesity related disease in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of tolcapone or a pharmaceutically acceptable salt or a prodrug thereof.

In the fifth aspect, disclosed herein is a method for controlling appetite and/or reducing food intake, for reducing weight gain and/or promoting weight loss, for reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or for use in preventing or treating obesity or an obesity related disease in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of tolcapone or a pharmaceutically acceptable salt or a prodrug thereof in combination with one or more different medicaments, e.g., for reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis, and a pharmaceutically acceptable excipient.

In the sixth aspect, disclosed herein is a pharmaceutical compositions comprising tolcapone or a pharmaceutically acceptable salt or a prodrug thereof in combination with one or more different medicaments, e.g., for reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis, or treating diabetes or hypoglycemia.

In an embodiment of the above first to sixth aspects, tolcapone or a pharmaceutically acceptable salt or a prodrug thereof is used as an FTO inhibitor.

In an embodiment of the above first to fifth aspects, the condition or disease in the method disclosed herein is FTO-related. For example, obesity or the obesity related disease is FTO-related, i.e., FTO-related obesity or hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases.

In an embodiment of the above first to sixth aspects, the subject is a patient which meets one or more criteria, such as (a) is not diagnosed with Parkinson's disease; (b) is less than 50, 40 or 30 years old; (c) is obese or over-weight; (d) suffers from or is diagnosed with an obesity related disease selected from diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular diseases, or liver, kidney or thyroid diseases; (e) has genotype: SNP rs7202116 (G) , rsl421085 (C) , or rs9939609 (A) ; and/or (f) pathogenically expresses or over-expresses FTO or Fto.

In another embodiment, the methods disclosed herein further comprise detecting in the person one or more of the criteria, particularly genotype SNP rs7202116 (G) , or over-expression of FTO or Fto.

In yet another embodiment, the method disclosed herein further comprise detecting a resultant reduction of food intake or appetite, inhibition of weight gain, promotion of weight loss, reduction of blood glucose and/or improvement or amelioration of one or more of the criteria.

In a particular embodiment, tolcapone in the methods and/or pharmaceutical composition disclosed herein is used in an amount of 0.1-4g, or g/day, or 0.2-4 g, or g/day.

All combinations of the particular embodiments recited herein are also contemplated, as if each had been separately, laboriously recited.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows enzymatic inhibition of tolcapone against FTO in the demethylase assay.

FIG. 2 shows tolcapone at the dose of 600mg/kg significantly inhibits food intake just after 2 days (P-value = 0.039) .

FIG. 3 shows tolcapone at the dose of 600mg/kg significantly decreases blood glucose after two weeks (P-value = 0.024) .

FIG. 4 shows tolcapone at the dose of 600mg/kg decreases body weight during the period of two weeks.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment of the first, second, third or fifth aspects, the subject is healthy. In another embodiment of the first, second, third or fifth aspects, the subject is suffering from diabetes, obesity or an obesity related disease.

In an embodiment of any of the aspects disclosed herein, the subject is a human.

In an embodiment of the methods disclosed herein of any of the aspects, the obesity related diseases include, but not limited to, diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases.

The methods and/or pharmaceutical compositions disclosed herein are also applicable to ameliorating or reducing the pathology or severity of an obesity related disease or a symptom of an obesity related disease selected from diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular diseases, or liver, kidney or thyroid diseases.

In the methods and/or pharmaceutical compositions disclosed herein, tolcapone is co-packaged, co-formulated or co-administered with one or more different medicaments for, specific for, or indicated for these related indications. The methods disclosed herein may further comprising detecting, determining or diagnosing in the person one or more of the indications, and/or detecting a resultant improvement or amelioration of corresponding condition or symptom in the person.

In an embodiment of the fifth aspect, tolcapone and the different medicament (s) are co-packaged, co-formulated or co-administered.

Preferred different medicaments for this purpose include, but not limited to,

a. Different anti-weight gain medicaments, particularly a food intake inhibitor and/or a food absorption inhibitor; particularly Orlistat, Cetilistat, Sibutramine, Lorcaserin, Rimonabant, Metformin, Exenatide, Liraglutide, Semaglutide, Pramlintide, Qsymia, Contrave or a pharmaceutically-acceptable salt thereof;

b. Medicaments for reducing serum LDL, cholesterol, LDL-c, or triglycerides or cholesterol lowering drugs, such as statins (including atorvastatin (Lipitor) , fluvastatin (Lescol) , lovastatin (Altoprev, Mevacor) , pravastatin (Pravachol) , rosuvastatin (Crestor) , simvastatin (Zocor) ) , or cholestyramine (Prevalite, Questran) , colesevelam (Welchol) , colestipol (Colestid) , ezetimibe (Zetia) , ezetimibe-simvastatin (Vytorin) , fenofibrate (Lofibra, TriCor) , gemfibrozil (Lopid) , Niacin (Niaspan) , Omega-3 fatty acid (Lovaza) , alirocumab, evolocumab or a pharmaceutically-acceptable salt thereof; and

c. Diabetes or hypoglycemia medicaments, such as insulin, glibenclamide, glipizide, gliquidone, gliclazide, glimepiride, glibornuride, repaglinide, nateglinide, metformin, acarbose, voglibose, rosiglitazone, pioglitazone, exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide, sitagliptin, saxagliptin, vildagliptin, alogliptin, linagliptin, anagliptin, teneligliptin, gemigliptin, trelagliptin, evogliptin, omarigliptin, canagliflozin, dapaglifozin, ipragliflozin, luseogliflozin, tofogliflozin, empagliflozin or a pharmaceutically-acceptable salt thereof.

In one embodiment of the first to fifth aspects disclosed herein, the subject is a human being which meets one or more criteria indicative of the disclosed non-Parkinson's indication, and the method may further comprising detecting in the person one or more of the criteria, and/or detecting a resultant reduction of food intake or appetite, inhibition of weight gain, promotion of weight loss, reduction of blood glucose and/or improvement or amelioration of one or more of such criteria.

Criteria indicative of the disclosed non-Parkinson's indication include wherein the person (a) is not suffering from, or is not diagnosed with Parkinson's disease or symptoms thereof or other prior indication for tolcapone or is not suffering from, or is not diagnosed with any degenerative disease of the central nervous system; (b) is less than 50, 40 or 30 years old; (c) is over-weight (e.g. a BMI of 25-30) or obese (e.g. a BMI of over 30) ; (d) suffers from, or is diagnosed with an obesity related disease selected from diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular diseases, or liver, kidney or thyroid diseases; or (e) has a genotype associated with obesity or pathogenic or medically-undesirable weight gain, such as SNP rs7202116 (G) , rsl421085 (C) , or rs9939609 (A) , or a surrogate or proxy SNP in linkage disequilibrium therewith (with respect to the correlative phenotype; see references below) and having a r ² value greater than 0.5; and/or (f) pathogenically expresses or over-expresses FTO or Fto (e.g. comprises and expresses a multi-copy fto gene) . Re rs7202116 G, see e.g. Yang et al., FTO genotype is associated with phenotypic variability of body mass index, Nature, Sep 16, 2012, doi: 10.1038/naturel l401 [epub] ; re rs9939609 A, see e.g. Freathy RM, et al (2008) . "Common variation in the FTO gene alters diabetes-related metabolic traits to the extent expected, given its effect on BMI" . Diabetes 57 (5) : 1419-26. doi: 10.2337/db07-1466. PMC 3073395. PMID 18346983; re rsl421085 C, see e.g. Dina C, et al., (2007) . "Variation in FTO contributes to childhood obesity and severe adult obesity" . Nature Genetics 39 (6) : 724-6. doi: 10.1038/ng2048. PMID 17496.

In another embodiment of the first to fifth aspects disclosed herein, the subject is a human being which does not suffer from a pathogenic deficiency of L-DOPA (L-3, 4-dihydroxyphenylalanine) , does not indicate L-DOPA, and/or is not in need of L-DOPA (levopoda) or a dopaminergic agent, and/or tolcapone is not administered in conjunction with L-DOPA or a doaminergic agent.

In an embodiment of the fifth aspect, the method further comprises administering to the person an effective amount of one or more additional, different medicament for reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis, particularly wherein the tolcapone and medicament (s) are co-packaged, co-formulated or co-administered.

In an embodiment of the sixth aspect, tolcapone and the one or more different medicaments are co-packaged or co-formulated or co-administered. In a preferred embodiment, the different medicament is a different anti-weight gain medicaments. For example, tolcapone and additional, different anti-weight gain medicaments may be co-formulated, particularly in unit dosage form, or unit dosage forms of each may be co-packaged in a multipack adapted for sequential use, such as blisterpack, comprising sheets of unit dosage forms. Exemplary co-formulation and co-packagings are shown in Table 1.

Table 1. Exemplary co-formulation and co-packagings.

1. Tolcapone /Orlistat in 600mg/120mg or 1200mg/120mg co-formulated tablets.

2. Tolcapone /Sibutramine in 600mg/10mg or 1200mg/10mg co-formulated tablets.

3. Tolcapone /Lorcaserin in 600mg/10mg or 1200mg/10mg co-formulated tablets.

4. Tolcapone /Rimonabant in 600mg/20mg or 1200mg/20mg co-formulated tablets.

5. Tolcapone /Metformin in 600mg/500mg or 1200mg/500mg co-formulated tablets.

6. Tolcapone /Exenatide: 600mg or 1200mg tablet /250 mcg/mL solution (Byetta) , co-packaged

7. Tolcapone /Exenatide: 600mg or 1200mg tablet /suspension powder, ER 2 mg (Bydureon) , co-packaged

8. Tolcapone /Pramlintide: 600mg or 1200mg tablet /600 mcg/mL (as acetate) , co-packaged

9. Tolcapone /Phentermine in 600mg/10mg or 1200mg/10mg co-formulated tablets.

10. Tolcapone /atorvastatin (Lipitor) in 600mg/10mg or 1200mg/10mg co-formulated tablets.

11. Tolcapone /fluvastatin (Lescol) in 600mg/80mg or 1200mg/80mg co-formulated tablets.

12. Tolcapone /lovastatin (Altoprev, Mevacor) in 600mg/10mg or 1200mg/10mg co-formulated tablets.

13. Tolcapone /pravastatin (Pravachol) in 600mg/10mg or 1200mg/10mg co-formulated tablets.

14. Tolcapone /rosuvastatin (Crestor) in 600mg/5mg or 1200mg/5mg co-formulated tablets.

15. Tolcapone /simvastatin (Zocor) in 600mg/10mg or 1200mg/10mg co-formulated tablets.

16. Tolcapone /cholestyramine (Prevalite, Questran) in 600mg/5000mg or 1200mg/5000mg co-packaged powder.

17. Tolcapone /colesevelam (Welchol) in 600mg/625mg or 1200mg/625mg co-formulated tablets.

18. Tolcapone /colestipol (Colestid) in 600mg/1000mg or 1200mg/1000mg co-formulated tablets.

19. Tolcapone /ezetimibe (Zetia) in 600mg/10mg or 1200mg/10mg co-formulated tablets.

20. Tolcapone /ezetimibe-simvastatin (Vytorin) in 600/10/10mg or 1200/10/10mg co-formulated tablets.

21. Tolcapone /fenofibrate (Lofibra, TriCor) in 600mg/54mg or 1200mg/54mg co-formulated tablets.

22. Tolcapone /gemfibrozil (Lopid) in 600mg/600mg or 1200mg/600mg co-formulated tablets.

23. Tolcapone /Niacin (Niaspan) in 600mg/500mg or 1200mg/500mg co-formulated tablets.

24. Tolcapone /Omega-3 fatty acid (Lovaza) 600mg/4mg or 1200mg/4mg co-formulated tablets.

25. Tolcapone /Cetilistat in 600mg/120mg or 1200mg/120mg co-formulated tablets.

26. Tolcapone /Liraglutide: 600mg or 1200mg tablet /solution containing 0.6mg, 1.2mg, 1.8mg, 2.4mg or 3mg of Liraglutide in prefilled, multi-dose pen (Victoza or Sexenda) , co-packaged.

27. Tolcapone /Semaglutide: 600mg or 1200mg tablet /solution containing 0.25 mg of Semaglutide (Ozempic) , co-packaged.

28. Tolcapone /Dulaglutide: 600mg or 1200mg tablet /solution containing 0.75mg/0.5mL or 1.5mg/0.5mL of Dulaglutide in single-dose pens or prefilled syringes (Trulicity) , co-packaged.

29. Tolcapone /Qsymia: 600mg or 1200mg tablet /Qsymia (phentermine/topiramate: 3.75mg/23mg or 7.5 mg/46 mg or 11.25 mg/69 mg or 15 mg/92 mg) co-formulated tablets, or co-packaged.

30. Tolcapone /Contrave: 600mg or 1200mg tablet /Contrave (Naltrexone/Bupropion: 8mg/90mg or 32mg/360mg) co-formulated tablets, or co-packaged.

31. Tolcapone /Alirocumab: 600mg or 1200mg tablet /solution containing 75mg or 150mg of Alirocumab in single-dose prefilled pen or syringe (Praluent) , co-packaged.

32. Tolcapone /Evolocumab: 600mg or 1200mg tablet /solution containing 140mg/mL of Evolocumab in single-use prefilled syringe or SureClick autoinjector (Repatha) , co-packaged.

33. Tolcapone /Sitagliptin: 600mg/100mg or 1200mg/100mg co-formulated tablets; 600mg/50mg or 1200mg/50mg co-formulated tablets; 600mg/25mg or 1200mg/25mg co-formulated tablets.

34. Tolcapone /Empagliflozin: 600mg/10mg or 1200mg/10mg co-formulated tablets; 600mg/25mg or 1200mg/25mg co-formulated tablets.

35. Tolcapone /Pioglitazone: 600mg/15mg or 1200mg/15mg co-formulated tablets; 600mg/30mg or 1200mg/30mg co-formulated tablets; 600mg/45mg or 1200mg/45mg co-formulated tablets;

36. Tolcapone /Glipizide: 600mg/10mg or 1200mg/10mg co-formulated tablets.

36. Tolcapone /Acarbose: 600mg/25mg or 1200mg/25mg co-formulated tablets.

By targeting different pathways the co-administered drugs can act supplementally or synergistically to increase the potency compared with separate administration, and thereby also permit use reduced or otherwise suboptimal or subtherapeutic dosages, if not co-administered, while maintaining efficacy, such as 50%/50%and 25%/25%co-formulations and co-packagings of those shown in Table 1.

In some embodiment of the first to sixth aspects disclosed herein, tolcapone is a prodrug thereof.

In some embodiment of the first to embodiment of the first to sixth aspects disclosed herein, tolcapone or a pharmaceutically acceptable salt or a prodrug thereof is optionally deuterated.

The term “pharmaceutically acceptable salts” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.

The term “prodrug” refers to a derivative of tolcapone that requires a transformation within the body to release the compound per se. In some embodiments, the transformation is an enzymatic transformation. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the active agent.

The term “deuterated” refers to one or more carbon-bound hydrogen (s) in tolcapone are replaced by one or more deuterium (s) . Similarly, the term “deuterated” is be used herein to modify the chemical structure or an organic group or radical of the tolcapone molecule, wherein one or more carbon-bound hydrogen (s) are replaced by one or more deuterium (s)

The compositions for administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, lozenges or the like in the case of solid compositions.

A wide variety of suitable formulations and delivery systems, including suitable excipients or carriers and methods for preparing administrable compositions, are known or apparent to those skilled in the art and are described in more detail in such publications as Remington: The Science and Practice of Pharmacy (Pharmaceutical Press (2012) . For example, in particular embodiments the compositions are formulated or delivered in extended or controlled delivery systems, such as diffusion systems (e.g. reservoir devices, matrix devices, diffusion-controlled implants and transdermal patches) and encapsulated and matrix dissolution systems, erosion products, osmotic pump systems, ion exchange resins, etc.

In an embodiment of the aspects disclosed herein, tolcapone is administered in an amount far in excess of, at least 1, 2, 3, 4 or 6X that (100mg) currently indicated for Parkinson's Disease, and will preferably be 0.1-8, 0.1-4, 0.1-2.5, 0.2-8, 0.2-4, 0.2-2.5, 0.3-8, 0.3-4, 0.3-2.5, 0.4-8, 0.4-4, 0.4-2.5, 0.6-8, 0.6-4, 0.6-2.5g/day, in unit dosage forms of 0.1, 0.2, 0.3, 0.4, 0.6g.

The compounds can be administered by a variety of methods including, but not limited to, parenteral, topical, oral, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment. Also, in accordance with the knowledge of the skilled clinician, the therapeutic protocols (e.g., dosage amounts and times of administration) can be varied in view of the observed effects of the administered therapeutic agents on the patient, and in view of the observed responses of the disease to the administered therapeutic agents.

The methods disclosed herein may also optionally include the antecedent step of determining that the person, particularly diagnosing and applicable disease or condition (herein) . In an embodiment of the aspects disclosed herein, the methods are useful in inhibiting FTO, reducing food intake or appetite, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or preventing or treating obesity or an obesity related disease.

Examples

The following descriptions of particular embodiments and examples are provided by way of illustration and not by way of limitation. Those skilled in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results.

Example 1: Enzymatic Inhibition

We measured compound inhibition activity in a demethylation reaction catalyzed by FTO. FTO-catalyzed demethylation activity was measured in a 100 μl reaction system containing 50 mM HEPES buffer (pH 7.5) , 100 μM a-KG, 100 μM (NH4) 2Fe (SO4) 2, 0.5 mM L-ascorbic acid, 50 μg/ml BSA, 0.5 μM ssDNA with m6A (5’-ATTGTCA (m6A) CAGCAGA-3’) , 0.1 μM FTO protein and different concentrations of tolcapone. The reaction system was incubated at 37℃ for 2h and was stopped by heating to 95℃ for 5 min. ssDNA was digested by nuclease P1 (Sigma) and alkaline phosphatase (Takara) . The concentrations of m6A and free A were analyzed by LC-MS/MS. The measured IC ₅₀ value of tolcapone against FTO is ～2.5 μM as shown in FIG. 1.

Example 2: In vivo Anti-diabetic Efficacy in genetically diabetic db/db mice

Tolcapone (600 mg/kg) was orally administered to 8 randomly selected male db/db mice by blending with normal diet, while the other 8 male db/db mice fed with normal diet as control group. After 2 weeks, the mean fasting plasma glucose of drug treatment group was significantly lower than that of control group (*p-value < 0.05) as shown in FIG. 3.

Example 3: In vivo Feeding Inhibition Efficacy in genetically diabetic db/db mice.

Tolcapone (600 mg/kg) was orally administered to 8 randomly selected male db/db mice by blending with normal diet, while the other 8 male db/db mice fed with normal diet as control group. After 2 days, the mean food intake of drug treatment group was significantly lower than that of control group (*p-value <0.05) as shown in FIG. 2, which is opposite to the finding with respect to entacapone.

Example 4: In vivo Anti-obesity Efficacy in genetically diabetic db/db mice

Tolcapone (600 mg/kg) was orally administered to 8 randomly selected male db/db mice by blending with normal diet, while the other 8 male db/db mice fed with normal diet as control group. The results in FIG. 4 shows that the mean body weight gain of the treatment group with tolcapone was less than that of the control group during the 14 day period.

Example 5: COMT Inhibition Assay

COMT inhibitory activity of tolcapone was confirmed by reaction kinetic model. The test compound (i.e., tolcapone) was diluted with assay buffer to desired concentration. The COMT enzyme was also diluted with assay buffer. Then 5 μL diluted test compound, 5 μL diluted COMT and 5 μL Esculetin were added into plate and incubated for 5 min at 37℃, sealed with TopSeal-A 384, Clear Adhesive (PE) . Then 5 μL AdoMet was added into the plate. The reaction system contains 1U COMT enzyme, test compound, 4 μM Esculetin, 0.6 mM AdoMet, 50 mM K3PO4, and 10 mM MgCl2. Read plate by using kinetics model (Excitation at 360 nm &emission at 460 nm) . The inhibition was calculated from the slope. The assay found that tolcapone has an IC50 value of 270.3 nM.

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 suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein, including citations therein, are hereby incorporated by reference in their entirety for all purposes.

Claims

A method for controlling appetite and/or reducing food intake, for reducing weight gain and/or promoting weight loss, for reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or for use in preventing or treating obesity or an obesity related disease, or ameliorating or reducing the pathology or severity of obesity or an obesity related disease or a symptom of obesity or an obesity related disease in a subject, comprising administering to the subject in need thereof a pharmaceutically effective amount of tolcapone or a pharmaceutically acceptable salt or a prodrug thereof.
The method of claim 1, wherein the obesity related disease is diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular disease, liver, kidney or thyroid diseases.
The method of claim 1, wherein tolcapone or a pharmaceutically acceptable salt or a prodrug thereof is administered in an amount of 0.1-8, 0.1-4, 0.1-2.5, 0.2-8, 0.2-4, 0.2-2.5, 0.3-8, 0.3-4, 0.3-2.5, 0.4-8, 0.4-4, 0.4-2.5, 0.6-8, 0.6-4, 0.6-2.5g/day
The method of claim 1, further comprising administering to the subject a pharmaceutically effective amount of one or more different medicaments for controlling appetite and/or reducing food intake, inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis or treating diabetes or hypoglycemia.
The method of claim 4, wherein tolcapone is co-packaged, co-formulated or co-administered with the one or more different medicaments.
The method of any one of claims 1-4, wherein the subject is healthy or suffering from diabetes, obesity or an obesity related disease.
The method of any one of claims 1-5, wherein the subject is a human being which meets one or more criteria:

(a) is not diagnosed with Parkinson's disease;

(b) is less than 50, 40 or 30 years old;

(c) is obese or over-weight;

(d) suffers from or is diagnosed with an obesity related disease selected from diabetes, hyperglycemia, diabetic nephropathy, hyperlipemia, coronary heart disease, atherosclerosis, hypertension, cardiovascular or cerebrovascular diseases, or liver, kidney or thyroid diseases;

(e) has genotype: SNP rs7202116 (G) , rsl421085 (C) , or rs9939609 (A) , or a surrogate or proxy SNP in linkage disequilibrium therewith and having a r2 value greater that 0.5; and/or

(f) pathogenically expresses or over-expresses FTO or Fto.
The method of any of claims 1-7, wherein tolcapone is used as an FTO inhibitor.
The method of any of claim 2, wherein the obesity related disease is FTO-related.
The method of claim 1 further comprising detecting in the person one or more of the criteria, particularly genotype SNP rs7202116 (G) , or over-expression of FTO or Fto.
A pharmaceutical compositions comprising tolcapone or a pharmaceutically acceptable salt or a prodrug thereof in combination with one or more different medicaments for controlling appetite and/or reducing food intake, for inhibiting weight gain, promoting weight loss, reducing blood glucose, reducing serum LDL, cholesterol, LDL-c, or triglycerides, or treating atherosclerosis, and a pharmaceutically acceptable excipient.