WO2008090534A1 - Methods and compositions for inhibition of excessive weight gain, reduction of inappropriate eating behaviours and inhibition of binge eating for the treatment of obesity - Google Patents

Abstract

The present invention relates to methods of and compositions for inhibition of excessive weight gain and reduction of inappropriate eating behaviours, and methods of and compositions for the treatment of obesity and disease characterised by abnormal weight gain. The methods and compositions are based on histone deacetylase (HDAC) inhibitors.

Description

Title

Methods and compositions for inhibition of excessive weight gain, reduction of inappropriate eating behaviours and inhibition of binge eating for the treatment of obesity Field of the invention

The present invention relates to methods of and compositions for inhibition of excessive weight gain and reduction of inappropriate eating behaviours, and methods of and compositions for the treatment of obesity and disease characterised by abnormal weight gain. The methods and compositions are based on histone deacetylase (HDAC) inhibitors. Background to the invention

Obesity can be defined simply as excessive fat accumulation in adipose tissue, to the extent that health may be impaired (Garrow JS. (1988) Obesity and related diseases. London, Churchill Livingston, pi -16), and, with a criterion of a body mass index (BMI) of >30, more than 30% of adults in the US are obese and more than 60% are overweight (BMI >25) (Flegal KM, Carroll MD, Ogden CL, Johnson CL. (2002). Prevalence and trends in obesity amongst US adults, 1999-2000. JAMA 288:1723- 1727). However, obesity is a complex disorder, which classification by body mass index fails to relate. Multiple factors contribute to the aetiology of the disease with dietary factors, physical activity patterns, other behavioural patterns, societal, emotional and environmental influences all contributing. Binge-eating disorder (BED), a behavioural disorder, occurs in 2 to 5 percent of nonobese individuals, but incidences of 23 to 46 percent have been reported in obese populations (Bulik CM, Sullivan PF, Kendler KS. (2003). Genetic and environmental contributions to obesity and binge eating. Int J Eat Disord. 33(3); 293-8). The criteria for BED are included in the Appendix to the DSM (DSM-IV-TR) and according to this an episode of binge eating is characterized, among other criteria, by eating, in a discrete period of time, an amount of food that is definitely larger than most people would eat in a similar period of time under similar circumstances. BED is a significant problem and correlates to poor long-term outcome in antiobesity treatments (Yanovski SZ. (1993) Binge eating disorder: current knowledge and future directions. Obes Res. 1(4); 306-24). Currently, amongst developed nations, obesity and overweight status represent the most common metabolic diseases, and are significant risk factors for co-morbid disease, including type 2 diabetes, and cardiovascular disease. The increasing prevalence of childhood and adolescent obesity suggests a trend to exacerbated obesity in future adults (Hedley AA, Ogden CL, Johnson CL, Carroll MD, Curtin LR, Flegal KM. (2004). Prevalence of overweight and obesity among US children, adolescents, and adults, 1999-2000. JAMA 291:2847-2850). The control of appetite and modulation of food intake are key in determining body weight, and as recently reviewed (Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW (2006). Nature 443; doi:10.1038), are the culmination of constant adaptations of various systems such as food seeking behaviour, satiety perception, energy homeostasis, food reward systems, brain reward circuitry, and potential for synaptic plasticity. Environmental factors, such as exposure to or availability of highly palatable foods of high caloric content, can exert significant effects on eating behaviours via activation of the brain reward systems that allow reinforcement of responses lacking homeostatic value. These inappropriate behavioural responses are not unlike those associated with chronic drug addiction (Saper CB, Chou TC, and Elmquist, (2002). The need to feed: homeostatic and hedonic control of eating. Neuron 36:199-211).

Such behavioural responses are exacerbated in pathological states which are genetically defined and may involve disruption of homeostatic mechanisms involved in control of food intake and metabolism. The regulation of energy balance is controlled by a complex interplay of physiological systems, which converge centrally in the hypothalamus. The best studied signalling factor is leptin, an adipocyte-derived cytokine, deficiency of which causes obesity in rodents and humans (Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. (1994). Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505); 425-32; Farooqi S, Rau H, Whitehead J, O'Rahilly S. (1999) ob gene mutations and human obesity. Proc Nutr Soc. 57(3); 471-5; Zhang Y and Scarpace PJ (2006) The role of leptin in leptin resistance and obesity. Physiol Behav. 88(3); 249-56), while conversely administration of leptin to young, lean rodents causes significant fat and weight loss (Elmquist JK, Maratos-Flier E, Saper CB, Flier JS. (1998). Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci. 1(6); 445-50). Leptin exerts its effects through the melanocortin pathway which involves neurons within the arcuate nucleus which express proopiomelanocortin (POMC). Leptin causes increases in a cleavage product of POMC, which acts on melanocortin 4 receptor (MC4R) expressing neurons in the hypothalamus, activation of which promotes catabolism by reducing food intake and increasing energy expenditure. This receptor can also be modulated in an antagonistic fashion by AgRP, whose expression in a distinct neuronal population of the arcuate nucleus is decreased by the action of leptin. Loss of function of this receptor results in obesity in mice and humans (Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F. (1997). Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 88(1); 131-41; Yeo GS, Farooqi IS, Aminian S, Halsall DJ, Stanhope RG, O'Rahilly S. (1998). A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat Genet. 20(2); 111-2). Therefore it is apparent that mutations at any stage of the leptin /melanocortin pathways can lead to obesity; mutations of leptin, the leptin receptor, POMC, and MC4R. A plethora of other peripheral signalling molecules exist, importantly, insulin, a product of pancreatic β cells, whose levels fall to signal starvation and rise in proportion to increasing obesity. Central administration of insulin suppresses food intake in rodents and subhuman primates and regulates expression of hypothalamic neuropeptides that modulate appetite. As such, a homeostatic disruption can further preclude an individual's ability to control body weight. Epidemiological, genetic and molecular studies of obese populations worldwide have suggested differing susceptibility to becoming overweight and obese. The role of genetic factors in weight gain is widely acknowledged and evidenced by studies such as those demonstrating that there is a higher concordance of BMI of adoptees with the BMI of their biological parents compared to their adoptive parents. Binge eating and obesity have been shown to have moderate and substantial heritability respectively, with only a modest overlap between the two (Bulik et ah, 2003). While the contribution of genetic factors to a predisposition to obesity is significant, monogenic or single mutations leading to obesity account for only a relatively small number of obese families (Clement K. (2006). Genetics of human obesity. C. R. Biologies 329; 608-622). Obesity with a polygenic cause, which is thought to underlie most common forms, entails a more complex interplay and involves a number of susceptibility alleles working together in a permissive environment to produce obesity. So while each susceptibility gene alone is not necessary or sufficient to induce obesity, and would individually have only a slight effect on weight, the combination of susceptibility genes and environmental factors can lead to development/ maintenance of obesity.

Current pharmaceutical strategies available for the treatment of obesity are limited. One class of compound, the best-known form being orlistat, inhibits pancreatic lipase and reduces dietary fat absorption. Although this results in significant weight loss orlistat has several gastrointestinal side-effects that limit its long-term use. The other class of compounds act centrally to reduce appetite. Of these, sibutramine, a noradrenergic and serotonin re-uptake inhibitor, reduces weight within the first 6 months of treatment. However, sibutramine administration is associated with elevated blood pressure and heart rate, such that its use is contraindicated in patients with uncontrolled hypertension, coronary heart disease, cardiac dysrhythmias, congestive heart failure or ischaemia (Kim SH, Lee Ym, Jee SH, Nam CM. (2003). Effect of sibutramine on weight loss and blood pressure: a meta-analysis of controlled trials. Obes Res 11:1116-1123). Only orlistat and sibutramine are currently licensed by the FDA for long-term obesity management, including weight loss and weight maintenance, and for reduction of the risk of weight regain after prior weight loss. Amphetamine treatment has also been utilised (Phentermine); FDA gave approval for its use as an appetite suppressant in 1959, however it was taken off the market in 1998 following discovery that there was an increased incidence of heart valve disease in users. Rimonabant, a CBl antagonist, has recently been shown to be well tolerated and effective in reducing body weight and improving cardiovascular and metabolic risk factors in both non-diabetic and diabetic overweight or obese patients (Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF (2006) Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 368; 1660-72). Treatment was associated with some adverse effects such as depressed mood disorder, nausea, and dizziness. While Rimonabant has been approved for sale by the European Commission, it is still under review to receive FDA approval. There is currently no effective treatment for BED although cognitive behavioural therapy can be helpful, as can be the use of antidepressants. To date, the possibility of treatment of obesity via epigenetic manipulation has not been investigated. Epigenetics is the study of factors that alter the phenotype without changing the genotype, for example, chromatin remodelling leading to altered gene expression patterns. One factor mediating epigenetic control concerns post- translational modification of histones. Histone acetylation is the best studied of these modifications, with a balance being maintained through addition of acetyl groups via histone acetyl tranferases and removal of these groups by histone deacetylases (HDACs; Thiagalingam S, Cheng KH, Lee HJ, Mineva N, Thiagalingam A, Ponte JF. (2003). Histone deacetylases: unique players in shaping the epigenetic histone code. Ann N Y Acad Sci. 983; 84-100).

This invention is based in the idea of epigenetic manipulation by use of a histone deacetylase inhibitor. This stems from two factors. Firstly, epigenetic manipulation can alter behavioural phenotype; rats receiving poor/ low maternal care as neonates exhibited more fearfulness, and an increased stress response, and this was correlated to low levels of glucocorticoid receptor expression, which was in turn correlated to high levels of DNA methylation and low levels of histone acetylation at the promoter region for this receptor. Both the epigenetic patterning and the fearful phenotype could be reversed by treatment with a HDAC inhibitor (Weaver IC, Meaney MJ, Szyf M. (2006). Maternal care effects on the hippocampal transcriptome and anxiety- mediated behaviors in the offspring that are reversible in adulthood. Proc Natl Acad Sci U S A. 103(9); 3480-5). We proposed that HDAC inhibition would also have potential for modulation of eating behaviour. Secondly, in an experiment examining behavioural changes induced by a HDAC inhibitor, we noted a significant decrease in weight gain in drug-treated animals. Incorporated into our rationale is the idea that there may be more than behavioural modifications occurring in HDAC inhibitor treated animals. Childhood obesity is strongly linked to parental obesity, and in terms of hereditary factors, epigenetic programming may play a significant role (Wu and Suzuki. (2006). Parental obesity and overweight affect the body-fat accumulation in the offspring: the possible effect of a high-fat diet through epigenetic inheritance Obes Rev 7; 201-208). The intrauterine environment and maternal nutrition appear to significantly effect offspring. Rats underfed in the first 2 weeks of pregnancy had apparently normal offspring until 5 weeks of age where the male progeny became hyperphagic and gained excess weight. Likewise pregnant Wistar rats fed a low-protein diet throughout pregnancy had offspring which preferentially consumed a high-fat diet. In a series of experiments it was demonstrated that a maternal high-fat diet before and during pregnancy produced offspring with an increased food consumption, weight gain, adiposity, and food efficiency, regardless of whether the offspring were fed a low or high-fat diet. This was also observed when offspring were suckled by foster dams on a normal diet, and even when fertilised eggs were taken from high-fat diet mothers and transplanted into foster dams on a normal diet. This indicates that an environmental effect of maternal diet even prenatally, predisposes offspring to obesity. While the mechanisms by which this occurs has not been elucidated, it is possible that diet- induced epigenetic changes which are passed to the next generation may mediate these effects. In support of the idea of diet-induced epigenetic change, it has previously been shown that when pregnant rats were fed a high methionine diet, phenotypic changes in coat colour of offspring were induced (Cooney CA, Dave AA, Wolff GL. (2002). Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. J Nutr. 132; 2393S-2400S). We suggest that HDAC inhibition may alleviate some of the underlying metabolic dysfunctions that culminate in obesity.

HDAC inhibition has the ability to modulate epigenetic control of transcription, and we proposed that this type of treatment would be of use in treating two key factors in obesity; inappropriate eating behaviours and binge-eating disorder, and the underlying metabolic state induced by monogenic or polygenic causes. Object of the invention

It is thus the object of the present invention to provide new methods and compositions for preventing excessive weight gain and reduction of inappropriate eating behaviours. In particular, it is an object to provide methods and compositions for the treatment of obesity and conditions characterised by abnormal eating habits, or abnormal weight gain. Summary of the invention According to the present invention there is provided use of at least one HDAC inhibitor in the manufacture of a medicament for the treatment of obesity, for the inhibition of excessive weight gain, for the reduction of inappropriate eating behaviours and/or for treatment of binge eating.

The invention also provides a pharmaceutical composition for treating obesity, for the inhibition of excessive weight gain, for the reduction of inappropriate eating behaviours and/or for treatment of binge eating, comprising at least one histone deacetylase inhibitor (HDAC).

In a further aspect the invention provides a method for treating obesity, excessive weight gain, inappropriate eating behaviours and/or binge eating comprising administering to a patient in need of such therapy a pharmaceutically effective amount of at least one histone deacetylase inhibitor

Histone deacetylase inhibitors or HDAC inhibitors, as that term is used herein are compounds that are capable of inhibiting the deacetylation of histones in vivo, in vitro or both. As such, HDAC inhibitors inhibit the activity of at least one histone deacetylase.

HDAC inhibitors suitable for use in the present invention can be categorised into six general classes: 1) hydroxamic acid derivatives; 2) short-chain fatty acids; 3) epoxy and non-epoxy ketone-containing cyclic tetrapeptides; 4) benzamides; 5) electrophilic ketones; and 6) miscellaneous HDAC inhibitors. However, any other class of compound capable of inhibiting histone deacetylases is suitable for use in the invention.

Examples of such HDAC inhibitors of each class include but are not limited to:

1) Hydroxamic acid derivatives such as: 3C1-UCHA: 6-(3-Chlorophenylureido) carpoic hydroxamic acid;

A-161906: CAS Registry No. 191228-04-3 (7-[(4'-cyano[l,l'-biphenyl]-4-yl)oxy]-N- hydroxy- heptanamide);

ABHA: CAS Registry No. 18992-11-5 (N,N'-dihydroxy-nonanediamide);

AAHA: (Azelaic-l-hydroxamate-9-anilide); CRA-A: CAS Registry No. 756486-62-1 (3'-[(dimethylamino)carbonyl]-N-hydroxy-

5'-[(4-methylbenzoyl)amino]- [l,l'-Biphenyl]-4-acetamide);

CBHA: CAS Registry No. 174664-65-4 (N-hydroxy-3-[3-(hydroxyamino)-3-oxo-l- propenyl]- benzamide);

JNJ16241199; 2-[4-(naphthalen-2-ylsulfonyl)piperazin-l-yl]pyrimidine-5- carbohydroxamic acid

LAQ-824: CAS Registry No. 591207-53-3 (N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-

(lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide);

MS344: CAS Registry No. 251456-60-7(4-(dimethylamino)-N-[7-(hydroxyamino)-7- oxoheptylj-benzamide); Oxamflatin: CAS Registry No. 151720-43-3 (N-hydroxy-5-[3-

[(phenylsulfonyl)amino]phenyi]-2-penten-4-ynamide);

Pyroxamide: CAS Registry No. 382180-17-8 (N-hydroxy-N'-3- pyridinyloctanediamide) ; PXDlOl: CAS Registry No. 414864-00-9 (N-hydroxy-3-[3-[(phenylamino)- sulfonyl]phenyl]- 2-propenamide);

SAHA: CAS Registry No. 149647-78-9 (N-hydroxy-N'-phenyl-octanediamide); SBHA: CAS Registry No. 38937-66-5 (N,N'-dihydroxy-octanediamide); Scriptaid: CAS Registry No. 287383-59-9 (N-hydroxy-l,3-dioxo-lH-Benz[de]- isoquinoline-2(3H)-hexanamide);

TSA: CAS Registry No. 58880-19-6 (7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6- dimethyl-7-oxo-2,4-heptadienamide); and

Tubacin: CAS Registry No. 537049-40-4 (N-[4-[(2R,4R,6S)-4-[[(4,5-diphenyl-2- oxazolyl)thio]methyl]-6-[4-(hydroxymethyl)phenyl]-l,3-dioxan-2-yl]phenyl]-N'- hydroxy-octanediamide) .

2) Short-chain fatty acids derivatives such as:

4-Phenyl butyrate: CAS Registry No. 4346-18-3 (phenyl ester butanoic acid);

AN-9: CAS Registry No. 122110-53-6 (Pivanex; (2,2-dimethyl-l-oxopropoxy) methyl ester butanoic acid);

Sodium butyrate: CAS Registry No. 156-54-7 (Butanoic acid, sodium salt);

Sodium phenyl butyrate;

Valproic Acid: CAS Registry No. 99-66-1 (2-propyl-pentanoic acid);

Isovalerate: CAS Registry No. 5711-68-2 (3-methyl-butanoic acid); Valerate: CAS Registry No. 10023-74-2 (Pentanoic acid);

Propionate: CAS Registry No. 72-03-7 (Propanoic acid);

Butyramide: CAS Registry No. 541-35-5 (Butanamide);

Isobutyramide: CAS Registry No. 563-83-7 (2-methyl-propanamide);

Phenylacetate: CAS Registry No. 7631-42-7 (Benzeneacetic acid); 3-bromopropionate: CAS Registry No. 16336-88-2 (3-bromo-propanoic acid); and

Tributyrin: CAS Registry No. 60-01-5 (1,2,3-propanetriyl ester-butanoic acid).

3) CyclicTetrapeptides such as: a) epoxy-ketone containing:

HC-toxin cyclic tetrapeptide: CAS Registry No. 83209-65-8 (Cyclo[L-alanyl- Dalanyl-(αS,2S)-α-amino-η-oxooxiraneoctanoyl-D-prolyl]);

Trapoxin A: CAS Registry No. 133155-89-2 (cyclic tetrapeptide (Cyclo[(αS,2S)-α- amino-η-oxooxiraneoctanoyl-L-phenylalanyl-L-phenylalanyl-(2R)-2- piperidinecarbonyl]). b) non epoxy-ketone containing: Apicidin: CAS Registry No. 183506-66-3 (Cyclo[(2S)-2-amino-8-oxodecanoyl-l- methoxy-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinecarbonyl]);

Chlamydocin CAS Registry No. 53342-16-8 (Cyclo[2-methylalanyl-L-phenylalanyl-

D-prolyl-(αS,2S)-α-amino-η-oxooxiraneoctanoyl]); CHAPs CAS Registry No. 618056-29-4 (general; Cyclo[(2S)-2-amino-8-

(hydroxyamino)-8-oxooctanoyl-L-phenylalanyl-L-phenylalanylprolyl]); and

Depsipeptide: CAS Registry No. 128517-07-7 (FK228; FK901228; Cyclo[(2Z)-2- amino-2-butenoyl-L-valyl-(3S,4E)-3-hydroxy-7-mercapto-4-heptenoyl-D-valyl-D- cysteinyl], cyclic (3→5)-disulfϊde). 4) Benzamide derivatives such as:

CI-994 CAS Registry No. 112522-64-2 (4-(acetylamino)-N-(2-aminophenyl)- benzamide); and

MS-275 CAS Registry No. 209783-80-2 ([[4-[[(2-aminophenyl)amino]carbonyl]- phenyl] methyl] -3 -pyridinylmethyl ester carbamic acid). 5) Electrophilic ketone derivatives such as: trifluoromethyl ketones; alpha-keto amides; alpha-keto oxazoles; and alpha-keto heterocycles.

6) Miscellaneous HDAC Inhibitors such as:

AOE (2-Amino-8-oxo-9,10-epoxydecanoic acid); Bromoacetamides;

Depudecin: CAS Registry No. 139508-73-9 (4,5:8,9-dianhydro-l,2,6,7,l l- pentadeoxy-D-threo-D-ido-undeco- 1 ,6-dienitol);

Methyl sulfoxides;

Mercaptoacetamides; N-formyl hydroxylamino;

Psammaplins;

Semi Carbazides;

Sulfur containing cyclic peptides (SCOPs);

Thiol derivatives; and others. Particularly preferred are the HDAC inhibitors SAHA and MS-275, or a combination therof.

It is understood that the present invention includes any salts, crystal structures, amorphous structures, hydrates, derivatives, metabolites, stereoisomers, structural isomers, polymorphs and prodrugs of the HDAC inhibitors described herein. This invention, in addition to the above listed compounds, is intended to encompass the use of homologues and analogues of such compounds. In this context, homologues are molecules having substantial structural similarities to the above-described compounds and analogues are molecules having substantial biological similarities regardless of structural similarities.

The invention also encompasses pharmaceutical compositions for inhibiting excessive weight gain and reduction of inappropriate eating behaviours comprising pharmaceutically acceptable salts of the HDAC inhibitors with organic and inorganic acids, for example, acid addition salts which may, for example, be hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic: acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid and the like. Pharmaceutically acceptable salts can also be prepared from the above by treatment with inorganic bases, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.

The invention also encompasses pharmaceutical compositions comprising hydrates of the HDAC inhibitors. The term "hydrate" includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like. The HDAC inhibitors can be in a crystalline form, in amorphous form, and have any particle size. The HDAC inhibitor particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.

Wherein said HDAC inhibitor is administered in the form of a pharmaceutical composition it may be prepared in admixture with one or more pharmaceutically acceptable excipients.

A pharmaceutical composition of the invention, which may be prepared suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants. For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or a pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0.1% to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration. The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.

The present invention is illustrated by reference to the following Examples: EXAMPLES EXPERIMENTAL PROTOCOL Animal maintenance

The obesity model utilised was Zucker 'fatty' rats, which involves a leptin pathway mutation. The spontaneous mutation "fatty" occurred in the Zucker laboratory and appeared to be due to a single recessive gene termed 'fa'. The disruption was proposed to be metabolic in origin, because while the "fatty" animals were hyperphagic, when they were restricted to a normal food intake, they were still obviously fat in appearance (Zucker and Zucker TF (1961) Fatty, a new mutation in the rat. Journal of hereditary 52; 275 - 278). Subsequently it has been demonstrated that the mutation results in a deficiency in the extracellular domain of the leptin receptor, which causes poor transport of the receptor to the cell surface, and reduced ligand affinity.

24 experimentally naive male Zucker rats were employed in this study. 12 were Zuckers of the fa/fa genotype (Fatty) and 12 were of the fa/- genotype (Lean). A second cohort of 18 fa/fa genotype (Fatty) and 6 fa/- genotype (Lean) were emploed in a subsequent experiment to examine additional HDAC inhibitors. The animals were supplied by Charles River Laboratories (France) and delivered to the Biomedical Facility, University College Dublin, on postnatal day 35. Animals were housed singly, and maintained at 22-24°C on a standard 12 hour light/dark cycle, with water available ad libitum. Food was obtained from Charles River so that the rats underwent no change in diet, and this was also available ad libitum. All animals were examined and weighed daily. All experimental procedures were approved by the Animal Research Ethics Committee of University College Dublin, and were carried out by individuals who retain the appropriate licences issued by the Irish Department of Health. Food intake

Food intake was monitored daily throughout the course of the experiment; every 24 hours, approximately 1 hour before onset of the dark cycle, food remaining in the food hopper was weighed. In addition, on postnatal days 41-45 and 69-73, food intake was assessed at 1 and 3 hours post darkness to determine any changes in eating behaviours. Drug administration

All studies were conducted using suberoylanilide hydroxamic acid (SAHA; Axxora Ltd. UK, batch number Ll 5785) and the benzamide derivative 4-[[(2- aminophenyl)amino]carbonyl]-phenyl]methyl]-3-pyridinylmethyl ester carbamic acid (MS-275; Axxora Ltd. UK, batch number L14358/a). . SAHA was administered daily from postnatal day 49 until 77 via the intraperitoneal route (i.p.) at 5 mg/kg dose in a 2 ml/kg volume of a 2-hydroxypropyl-beta-cyclodextrin vehicle (9g/L). ). In a second experimental cohort the same SAHA dose but also MS-275 administered at 1 mg/kg in a 2 ml/kg dose volume of ClH₂O vehicle (solubility was assisted by first dissolving the MS-275 with a drop of 100% glacial acetic acid and adjusting the pH to 6.6 with the addition of NaOH). Injections occurred approximately 1 hour before onset of the dark cycle. Vehicle-treated controls were employed for comparison. Open field assessment

Spontaneous behaviour was assessed in an open-field apparatus for 5 minutes. The open-field apparatus consisted of black-painted wood 620mm² with walls 150mm high. The floor of the apparatus was ruled from side to side, dividing it into a series of boxes 77mm². Locomotor activity was measured as the number of lines crossed in a 300 second period.

EXAMPLE 1: Effect of the histone deacetylase inhibitor suberoylanilide hvdroxamic acid TSAHA) on weight gain and 4-ff(2- aminophenvI)aminolearbonvπ-phenvπmethvI1-3-Pyridinylmethyl ester carbamic acid (MS-275) on weight gain Animals maintained in accordance with the general procedure outlined in section (a) above were administered suberoylanilide hydroxamic acid (SAHA; 5 mg/kg), 4-[[(2- aminophenyl)amino]carbonyl]-phenyl]methyl]-3-pyridinylmethyl ester carbamic acid (MS-275, 1 mg/kg), or vehicle (2-hydroxypropyl-beta-cyclodextrin; 9g/L) via the intraperitoneal route (i.p.) for 28 days, starting on postnatal day 49. In order to assess the influence of the histone deacetylase inhibitor SAHA on weight gain animals were weighed daily. The mean actual weight gained over the 28 days of the experiment is shown in Table 1. Additionally, mean daily weights (expressed as a percentage of the animals weight on first day of dosing) are shown for each day (Table 3). These data demonstrate the significant difference between Fatty vehicle- treated animals and Lean vehicle-treated animals in actual weight gain and in percentage weight gain over time (Two-way ANOVA; F[l,18]=112.2; pO.OOOl and Two-way ANOVA; F[l,280]=20.0; p= 0.0012 respectively). Furthermore, it is demonstrated that SAHA administration ameliorates the weight gain exhibited by Fatty animals with a significant effect of drug (Two-way ANOVA; F[l,18]=12.43; p<0.0024). When this is expressed as percentage weight gain, SAHA-treated Fatty animals exhibit a weight gain pattern significantly different to vehicle-treated Fatty animals (Two-way ANOVA; F[1, 252]= 7.89; p=0.024), but similar to vehicle-treated Lean animals (Two-way ANOVA; F[l,252]= 0.0009; p=0.98). SAHA treatment exerted no significant effect on weight gain of Lean animals. MS-275 when administered according to the same treatment regimen resulted in similar results. Again a significant increase in total and percentage weight gain (Figures 2 and 4) was reported in Zucker Fatty-vehicle-treated animals as compared to Zucker Lean vehicle-treated animals (T-Test; PO.0001 and Two-way ANOVA; F[l,290]=27.38; P=0.0004). MS-275 administration ameliorates the weight gain exhibited by Fatty animals (Table 2; T-test; p=0.0062). Analysed by percentage weight gain, MS-275 treated Fatty animals exhibit a weight gain significantly lower than vehicle-treated Fatty animals (Table 4; Two-way ANOVA; F[l,290]=19.93; p=0.0012), but similar to vehicle-treated Lean animals (Two-way ANOVA; F[l,290]=1.39; p=0.27). Moreover, analysis of total weight gain (Table 2; T-test; P=0.03) and percentage weight gain (Table 4; F[l,300]=5.4; p=0.02) indicates MS- 275 administration to have a significantly greater amelioration effect on fatty animal phenotype as compared to SAHA treatment. TABLE 1

Fatty Lean

SAHA (mg/kg) - 5 - 5

mean SEM mean SEM mean SEM mean SEM

143.1 3.03 123.3 6.55 95.5 1.82 87.6 3.79

Data represent mean weight gain (g) ± SEM from start of drug administration to end of experiment. (n=6 for all groups)

TABLE 2

Lean Fatty

SAHA (5mg/kg) +

MS-275 (1 mg/kg) _

mean SEM mean SEM mean SEM mean SEM

91.1 3.82 153.0 8.55 136.3 4.91 121.1 3.48 Data represent mean weight gain (g) ± SEM from start of drug administration to end of experiment. (n=6 for all groups) TABLE 3

f ^ratty Lean

SAHA (mg/kg) - 5 - 5

Day no. mean SEM mean SEM mean SEM mean SEM

0 100.0 0.02 100.0 0.00 100.0 0.00 100.0 0.00

1 102.9 0.30 102.4 0.68 102.7 0.42 103.0 0.34

2 105.7 0.34 103.6 0.70 105.9 0.27 104.3 0.66

3 109.3 0.40 106.6 0.66 109.2 0.34 107.3 0.82

4 111.4 0.47 108.3 0.76 111.7 0.52 109.0 0.70

5 114.1 0.43 110.7 0.70 113.6 0.56 110.7 0.74

6 117.7 0.69 112.9 0.80 116.5 0.58 112.8 0.80

7 119.8 0.55 115.1 1.03 118.1 0.68 114.8 1.07

8 122.0 0.83 117.8 1.04 120.0 0.77 116.8 0.89

9 125.2 0.78 119.9 1.17 121.7 0.44 117.7 1.26

10 127.2 0.93 121.6 1.07 123.7 0.72 119.6 1.05

11 129.0 1.08 123.5 1.60 124.7 0.47 121.2 1.11

12 133.5 1.22 125.8 1.83 128.1 0.59 123.6 1.51

13 134.7 1.30 128.0 1.75 129.1 0.62 125.3 1.55

14 136.5 1.41 129.9 2.07 131.0 0.79 126.6 1.79

15 138.5 1.45 131.8 1.82 131.5 0.49 128.2 1.90

16 141.0 1.70 133.7 2.18 133.6 0.78 132.5 4.47

17 143.4 1.71 136.0 2.72 135.1 0.78 131.0 2.22

18 145.2 1.84 138.8 2.51 136.4 0.68 133.6 2.20

19 146.4 2.33 139.1 2.58 138.4 1.01 133.9 2.15

20 149.4 2.06 141.0 2.83 139.8 0.75 135.5 1.96

21 150.3 1.94 142.1 2.47 140.9 0.96 137.5 2.23

22 152.1 2.26 143.5 2.97 142.8 1.10 138.0 2.09

23 155.2 2.45 146.4 3.21 143.8 1.29 139.5 2.23

24 158.1 2.24 149.2 3.35 146.2 1.20 141.2 2.04

25 160.8 2.36 151.4 3.44 147.3 1.09 143.1 2.21

26 163.2 2.17 152.6 3.27 149.0 1.09 144.3 2.29

27 163.5 2.34 154.5 3.84 150.6 0.94 146.2 1.98

28 168.1 2.25 156.3 4.04 152.5 1.00 147.9 2.15

Data represent mean percentage weight gain (g) ± SEM (n=6 for all ! groups) TABLE 4

Lean Fatty

SAHA (5mg/kg) - - -

MS-275 (1mg/kg) - - - +

Day no. mean SEM mean SEM mean SEM mean SEM

0 100.0 0.00 100.0 0.00 100.0 0.00 100.0 0.00

1 101.7 0.42 100.8 0.46 100.7 0.44 101.6 0.24

2 103.4 0.38 103.7 0.65 102.4 0.45 104.3 0.41

3 105.3 0.36 106.1 0.66 104.3 0.42 104.3 0.52

4 106.1 0.46 108.0 0.90 105.4 0.87 105.7 0.63

5 110.3 0.57 111.6 1.06 107.9 1.21 108.1 0.65

6 112.3 0.59 114.4 0.93 109.6 1.05 111.6 0.71

7 113.1 0.71 115.5 0.86 110.0 1.00 111.3 0.56

8 114.8 0.63 117.4 0.93 111.4 1.17 113.4 0.84

9 116.4 0.69 120.1 1.11 114.0 0.99 115.5 0.64

10 118.0 0.67 122.2 0.93 115.4 1.10 116.7 1.09

11 120.1 0.86 124.3 0.90 118.5 1.16 118.7 0.97

12 120.7 0.64 126.4 0.99 121.0 1.26 120.7 1.05

13 122.6 0.85 128.3 0.89 123.0 1.14 123.1 1.28

14 123.7 1.19 130.5 0.95 125.0 1.60 125.0 1.30

15 125.4 0.91 132.4 1.04 127.1 1.46 127.1 1.18

16 127.0 1.15 134.3 1.01 128.6 1.92 128.1 0.96

17 127.8 1.05 136.3 1.13 130.7 1.64 130.0 1.31

18 128.7 1.07 138.2 1.23 132.5 1.75 131.4 1.41

19 129.0 0.87 139.4 1.15 133.7 1.86 131.9 1.39

20 131.5 1.17 141.7 1.63 135.6 1.74 134.0 1.26

21 132.2 1.36 142.7 1.55 137.6 2.04 134.7 1.21

22 133.6 1.10 144.8 1.56 138.9 2.06 136.2 1.24

23 133.9 1.24 146.8 1.42 141.0 2.06 137.9 1.23

24 135.2 1.09 148.2 1.51 142.5 2.20 139.2 1.41

25 135.9 1.22 150.0 1.75 144.2 2.25 141.4 1.35

26 137.2 1.33 155.5 1.70 145.3 2.10 141.7 1.29

27 139.1 1.75 155.5 1.97 147.1 1.94 143.9 1.31

28 139.2 2.05 155.9 1.96 148.0 2.01 143.9 1.45

29 141.2 1.58 156.8 1.97 149.8 2.16 146.0 1.36

Data represent mean percentage weight gain (g) ± SEM (n=6 for all groups). EXAMPLE 2: Effect of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) and 4-llT2-aminophenvI)aminolcarbonyri- phenvπmethvH-3-pyridinyImethyl ester carbamic acid (MS-275) on food intake

To determine the effect of the histone deacetylase inhibitor SAHA on food intake, food was weighed every 24 hours. Average food intake over each week for each group is shown in Table 5. Week 1 represents a pre-treatment period, while during weeks 2-5 animals were receiving drug or vehicle daily. A significant effect of genotype on total food intake was observed between Fatty and Lean vehicle-treated animals (Two-way ANOVA; F[l,48]=596.1; pO.OOOl) with significant differences observed at each timepoint (Bonferroni post tests; pO.OOl in each case). Over the 4 weeks of drug administration, SAHA treatment was shown to cause a significant reduction in food intake by Fatty animals (Two-way ANOVA; F[l,48]=8.33; p=0.014) but this was only significant in week 2 (Bonferroni post test; p<0.01). SAHA treatment had no effect on food intake by Lean animals (Two-way ANOVA; F[l,48]=2.35; p=0.15). This suggests that the actual effect of SAHA on total food intake over 24 hours is minimal, and restricted to the first week of drug onboard (week 2).

TABLE 5

Fatty Lean

SAHA (mg/kg) - 5 - 5

Week no. mean SEM mean SEM mean SEM mean SEM

1 23.40 0.51 24.20 0.69 17.70 0.56 17.30 0.57

2 24.00 0.27 21.20 0.57 17.40 0.24 15.60 0.54

3 25.70 1.67 24.70 1.33 17.50 1.11 16.80 1.04

4 27.30 0.62 26.30 0.67 17.40 0.52 17.70 0.41

5 27.50 1.85 27.40 1.57 19.00 0.51 18.90 0.83

Data represents mean food intake (g) of 6 animals over 7 days ± SEM (n=6 for all groups). In a second cohort of animals, to determine the effect of the histone deacetylase inhibitor MS-275 on food intake, food was weighed every 24 hours. Average food intake over each week of drug treatment for each group is shown in Table 6. As previously reported a significant effect of genotype on total food intake was observed between Fatty and Lean vehicle-treated animals (Two-way ANOVA; F[l,36]=185.8; pO.OOOl) with significant differences observed at each timepoint (Bonferroni post tests; p<0.001 in each case). Over the 4 weeks of drug administration, MS-275 treatment was shown to cause a significant reduction in food intake by Fatty animals (Two-way ANOVA; F[l,36]=45.8; pO.OOOl) significant at each week of treatment (Bonferroni post test; pO.Ol). Although SAHA again reduced food intake (Two-way ANOVA; F[l,36]=7.8; p=0.017) the effect of MS-275 was significantly greater (Two- way ANOVA; F[l,36]=16.2; p=0.0017).

TABLE 6

Lean Fatty

SAHA (5mg/kg) - - -

MS-275 (1mg/kg) - - - +

Week no. mean SEM mean SEM mean SEM mean SEM

1 21.4 1.11 28.5 1.34 25.0 1.67 24.2 1.78

2 22.6 0.43 30.9 0.44 29.7 0.81 26.6 0.53

3 20.9 0.51 29.3 0.70 29.2 0.61 25.1 0.48

4 21.4 1.09 30.5 1.13 28.4 0.96 24.8 0.67 Data represents mean food intake (g) of 6 animals over 7 days ± SEM (n=6 for all groups).

Food intake was assessed in more detail on days p41-p45 (pre-treatment) and p69-p73 (post 21 days drud administration); food intake was assessed at 1, 3, and 24 hours post onset of darkness to determine any changes in eating behaviours. Average food intake over 5 days at the 1, 3 and 24 hour post darkness timepoints is shown in Table 7. The postnatal day 41-45 period represents a pretreatment stage and as such shows pooled data for the Fatty and Lean groups, as no significant differences were found between the subgroups. For p41-p45 Fatty animal food intake was significantly greater than Lean animal food intake at all timepoints; 1, 3 and 24 hours post darkness (unpaired student t test; pO.OOOl in each case).

Following 21 days drug treatment, food intake was assessed for the p69-p73 at the same timepoints of 1, 3 and 24 hours. At the 24 hour timepoint for p69-p73 (drug onboard), while there remained a significant difference between Fatty and Lean animal food intake (Two-way ANOVA; F[l,16]=348.9; pO.OOOl), drug treatment exerted no significant effect (Two-way ANOVA; F[l,16]=1.197; p=0.29). This demonstrates that SAHA treatment appeared to have no effect on total amount of food eaten over a 24-hour period. However, SAHA treatment did appear to have an effect on the pattern of eating behaviour observed. Food intake in the first hour post darkness was significantly effected by genotype (Two-way ANOVA; F[l,16]=18.73; p=0.0005) and also by SAHA treatment (Two-way ANOVA; F[l,16]=16.29; p=0.001), more specifically post hoc analysis revealed significant differences between Fatty and Lean vehicle-treated animals, but not between Fatty and Lean animals treated with SAHA (Bonferroni post test; pO.OOl, p>0.05 respectively). This indicates that SAHA treatment could affect a change from a Fatty animal phenotype of eating behaviour to a Lean animal phenotype. A similar data set were observed at the 3 hour timepoint; food intake in the first 3 hours post darkness was significantly effected by genotype (Two-way ANOVA; F[l,16]=27.07; pO.OOOl) and also by SAHA treatment (Two-way ANOVA; F[l,16]=10.11; p=0.0058), more specifically post hoc analysis revealed significant differences between Fatty and Lean vehicle- treated animals, but not between Fatty and Lean animals treated with SAHA (Bonferroni post test; pO.OOl, p>0.05 respectively). In the second experimental cohort, MS-275 administration also significantly reduced the amount of food consumed by Fatty animals in the periods post-darkness (Table 8; Two-way ANOVA; F[l,24]=57.1; pO.OOOl). Analysis by Bonferroni post test indicates significant reduction in food intake at 3 and 24 hours post-darkness (PO.06). A trend to significance was noted at the 1 hour post-darkness timepoint (p=0.06). As such, MS-275 enabled a significant reduction in total food intake in Fatty animals, when compared to vehicle treated animals. Moreover, this decrease in food intake was greater than that of SAHA-treated Fatty animals (F[l,24]=26.7; pO.OOOl). TABLE 7

Time Period p41 - p45 p69 - p73

Genotype Fatty Lean Fatty Lean

SAHA (mg/kg) - - 5 - 5

Time post mean SEM mean SEM mean SEM mean SEM mean SEM mean SEM darkness (hours)

1 1 9 0 11 1 1 0 10 2 17 0229 1 09 0 138 1 05 0 152 0 84 0076 3 4 8 0 12 37 0 11 6 97 0433 496 0 248 4 25 0 245 4 01 0 435 24 234 048 17 2 0 50 2779 0464 26 98 0 342 18 83 0 616 18 63 0 380

Data represents mean food intake (g) of 12 (p41-p45) or 6 (p69-p73) animals over 5 days ± SEM

TABLE 8

Genotype Lean Fatty

SAHA (5mg/kg) - - + -

MS-275 (1 mg/kg) - - - +

Time post mean SEM mean SEM mean SEM mean SEM darkness (hours)

1 2 17 0 229 1 09 0 138 1 05 0 152 0 84 0 076

3 6 97 0 433 4 96 0248 4 25 0 245 4 01 0 435

24 27 79 0 464 26 98 0 342 18 83 0 616 18 63 0 380

Data represents mean food intake (g) of 12 (p41-p45) or 6 (p69-p73) animals over 5 days ± SEM

In summary with the histone deacetylase inhibitors SAHA (5mg/kg) or MS-275 (1 mg/kg) affects a change from a Fatty animal phenotype to a Lean animal phenotype with respect to percentage weight gain and eating behaviour post onset of darkness.

Effect of the histone deacteylase inhibitor suberoylanilide hydroxamic acid

(SAHA^") on open-field behaviour.

Animals were introduced to the open-field apparatus on postnatal days p40 and p41 (prior to drug treatment) and on days p68 and p69 (drug onboard). Over days p40 and p41, both Fatty and Lean animals showed significant habituation (Table 9; paired student t test; p= 0.005 and p<0.0001 respectively). Fatty animals were significantly less active than lean animals on both p40 and p41 (Table 9; unpaired student t test; pO.0001 and p=0.0008 respectively).

TABLE 9

Fatty Lean

Day mean SEM mean SEM p40 101.0 7.04 155.3 6.71 p41 73.0 6.64 108.6 6.33 Data represents mean ± SEM of the number of lines crossed over a 5-minute period in the open-field apparatus (n=12 for each group).

Over days p68 and p69, both Fatty and Lean animals showed significant habituation (Table 10; Two-way ANOVA; F[l,10]=185.4; pO.0001 and F[l,10]=30.16; p= 0.0003 respectively) but drug treatment exerted no effect. Fatty animals were significantly less active than leans on both day p68 and p69 (Table 10; Two-way ANOVA; F[l,20]=9.67; p=0.0055 and F[l,20]=5.48; p=0.0297 respectively) but again drug treatment exerted no effect on these trends. TABLE lO

Fatty Lean

- 5 - 5

Day mean SEM mean SEM mean SEM mean SEM p68 100.0 8.49 89.3 10.01 128.3 9.40 121.3 10.77 p69 57.0 4.28 53.7 8.12 73.7 5.04 66.7 7.13

Data represents mean ± SEM of the number of lines crossed over a 5-minute period in the open-field apparatus (n=6 for each group).

Claims

Claims

1. Use of at least one HDAC inhibitor in the manufacture of a medicament for the treatment of obesity, for the inhibition of excessive weight gain, for the reduction of inappropriate eating behaviours and/or for treatment of binge eating.

2. A pharmaceutical composition for treating obesity, for the inhibition of excessive weight gain, for the reduction of inappropriate eating behaviours and/or for treatment of binge eating, comprising at least one histone deacetylase inhibitor (HDAC).

3. A method for treating obesity, excessive weight gain, inappropriate eating behaviours and/or binge eating comprising administering to a patient in need of such therapy a pharmaceutically effective amount of at least one histone deacetylase inhibitor

4. The use, a pharmaceutical composition or a method of treatment as claimed in any preceding claim wherein the HDAC inhibitor is selected from the group consisting of a hydroxamic acid derivative, a short chain fatty acid, a cyclic tetrapeptide, a benzamide derivative, an electrophilic ketone derivative or any other class of compounds capable of inhibiting histone deacetylases.

5. The use, a pharmaceutical composition or a method of treatment as claimed in claim 4 wherein the HDAC inhibitor is a hydroxamic acid derivative selected from the group consisting of :-

6-(3-Chlorophenylureido) carpoic hydroxamic acid;

7- [(4'-cyano [1,1 '-biphenyl] -4-yl)oxy] -N-hydroxy-heptanamide ;

N,N'-dihydroxy-nonanediamide;

Azelaic-l-hydroxamate-9-anilide; 3'-[(dimethylamino)carbonyl]-N-hydroxy-5'-[(4-methylbenzoyl)amino]-[l,r-

Biphenyl]-4-acetamide;

N-hydroxy-3 - [3 -(hydroxyamino)-3 -oxo- 1 -propenyl] -benzamide ;

N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(lH-indol-3-yl)ethyl]amino]methyl]phenyl]-2- propenamide; 4-(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]-benzamide; N-hydroxy-5 - [3 - [(phenylsulfonyl)amino]phenyl] -2-penten-4-ynamide ; N-hydroxy-N'-3-pyridinyl-octanediamide; N-hydroxy-3-[3-[(phenylamino)sulfonyl]phenyl]-2-propenamide; N-hydroxy-N'-phenyl-octanediamide; N,N'-dihydroxy-octanediamide;

N-hydroxy-l,3-dioxo-lH-Benz[de]isoquinoline-2(3H)-hexanamide; 7-[4-(dimethylamino)phenyl]-N-hydroxy-4,6-dimethyl-7-oxo-2,4-heptadienamide; and (N-[4-[(2R,4R,6S)-4-[[(4,5-diphenyl-2-oxazolyl)thio]methyl]-6-[4-(hydroxy - methyl)phenyl] -1,3 -dioxan-2-yl]phenyl] -N'-hydroxy-octanediamide

6. The use, a pharmaceutical composition or a method of treatment as claimed in claim 4 wherein said HDAC inhibitor is a short Chain Fatty Acid selected from the group consisting of 4-Phenyl butyrate, 2,2-dimethyl-l-oxopropoxy) methyl ester butanoic acid, Sodium butyrate, Sodium phenyl butyrate, Valproic Acid, isovalerate, valerate, propionate, butyramide, isobutyramide, phenylacetate, 3-bromopropionate, and tributyrin.

7. The use, a pharmaceutical composition or a method of treatment as claimed in claim 4 wherein the HDAC inhibitor is a Cyclic Tetrapeptide selected from the group consisting of HC-toxin cyclic tetrapeptide, Trapoxin A, Apicidin, Chlamydocin, CHAPs, Depsipeptide, and FR225497.

8. The use, a pharmaceutical composition or a method of treatment as claimed in claim 4 wherein the HDAC inhibitor is a Benzamide derivative selected from the group consisting of CI-994, MS-275 and a 3 '-amino derivative of MS-27-275.

9. The use, a pharmaceutical composition or a method of treatment as claimed in claim 4 wherein the HDAC inhibitor is an electrophilic ketone derivative selected from the group consisting of trifluoromethyl ketones, alpha-keto oxazoles, alpha-keto heterocycles and alpha-keto amides.

10. The use, a pharmaceutical composition or a method of treatment as claimed in claim 4 wherein the HDAC inhibitor is selected from the group consisting of 2- Amino-8-oxo-9,10-epoxydecanoic acid); Bromoacetamides; Depudecin: (4,5:8,9- dianhydro-l,2,6,7,l l-pentadeoxy-D-threo-D-ido-undeco-l,6-dienitol); Methyl sulfoxides; Mercaptoacetamides; N-formyl hydroxylamino; Psammaplins; Semi Carbazides; Sulfur containing cyclic peptides (SCOPs); and Thiol derivatives.

11. The use, a pharmaceutical composition or a method of treatment as claimed in any of claims lto 4 wherein the HDAC inhibitor is SAHA or MS-275.

12. The method of any of claims 311, wherein the HDAC inhibitor is administered orally, parenterally, intraperitoneally, intracerebroventricularly, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, via inhalation, vaginally, intraoccularly, locally, subcutaneously, intraadiposally, intraarticularly, intrathecally.

13. The composition of any of claims 3 - 12, wherein the HDAC inhibitor is in a slow release dosage form.