WO2013117693A1

WO2013117693A1 - Pde4 inhibitor for treating huntington's disease

Info

Publication number: WO2013117693A1
Application number: PCT/EP2013/052537
Authority: WO
Inventors: Anthony Richard RUTTER
Original assignee: GlaxoSmithKline Intellectual Property Development Ltd
Current assignee: GlaxoSmithKline Intellectual Property Development Ltd
Priority date: 2012-02-10
Filing date: 2013-02-08
Publication date: 2013-08-15
Anticipated expiration: 2014-08-10

Description

PDE4 INHIBITOR FOR TREATING HUNTINGTON'S DISEASE

This invention relates to the use of pyrazolopyridine derivatives for the symptomatic treatment and disease modification of Huntington's disease.

The family of phosphodiesterase (PDE) enzymes hydrolyse the cyclic nucleotide intracellular second messengers, cAMP and cGMP leading to their inactivation. Inhibition of these enzymes leads to elevated levels of cAMP and cGMP in the cell and prolongs their action on downstream signalling pathways. Signalling through these second messengers has been implicated in the pathophysiology of diseases and disorders such as depression, and has been shown to be involved in the therapeutic action of existing antidepressant drugs (Tardito, D. et al (2006) Pharmacol. Rev. 58(1 ) pp1 15-134; Dlaboga, D. et al (2006) Brain Res. 1096(1 ) pp104-1 12).

The PDE family consists of eleven subtypes (PDE1 to PDE1 1 ). These eleven subtypes differ in their ability to hydrolyse cAMP and/or cGMP, their tissue and intracellular distribution, their sensitivity to intracellular modulators and their inhibitor pharmacology. Each subtype exists as multiple forms generated by different genes and by alternative splicing of the N-terminus.

The PDE4 subtype consists of four isoforms (PDE4A to PDE4D), which can be further divided on the basis of splicing differences (O'Donnell, J.M. and Zhang, H.T. (2004) Trends Pharmacol. Sci. 25(3) pp158-163). The PDE4A, PDE4B and PDE4D isoforms are predominantly found in the brain, where they are expressed widely, but differentially. PDE4A, PDE4B and PDE4D knockout mice show differences with respect to wild type animals in growth and survival, fertility, airway hypereactivity, inflammatory response, myocyte contraction and neurological function, consistent with the wide distribution and role of PDE4 enzymes (Houslay, M.D. et al (2005) Drug Discovery Today 10(22) pp1503-1519).

PDE4 inhibitors, such as the prototypical brain-penetrant inhibitor rolipram, influence central function in animals in a dose-dependent manner, consistent with their potential use in the treatment of depression and cognitive disorders in humans. However higher doses of these compounds can give rise to mechanism-related side effects such as emesis, sedation and vascular inflammation.

The pyrazolopyridine compounds disclosed in WO04/056823 are phosphodiesterase 4 (PDE4) inhibitors. The compounds are disclosed as being useful for the treatment or prophylaxis of inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or allergic rhinitis. WO201 1/107394 discloses the use of a compound of formula (I): 5-{5-[(2,4-dimethyl-1 ,3- thiazol-5-yl)methyl]-1 ,3,4-oxadiazol-2-yl}-1-ethyl-/V-(tetrahydro-2H-pyran-4-yl)-1 H- pyrazolo[3,4-b]pyridin-4-amine

(I) or a pharmaceutically acceptable salt thereof for the treatment or prophylaxis of an anxiety disorder. WO201 1/107394 discloses that 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5- yl)methyl]-1 ,3,4-oxadiazol-2-yl}-1 -ethyl-/V-(tetrahydro-2H-pyran-4-yl)-1 /-/-pyrazolo[3,4- b]pyridin-4-amine may provide a greater therapeutic window between said anxiolytic effects and nausea or other mechanism-related side effects. This compound is disclosed in WO2004/056823 as Example 98.

Huntington's disease is the most common genetic cause of abnormal involuntary writing movements (chorea). It is a neurodegenerative disorder, with massive atrophy of the striatum being the characteristic pathological feature of the disease. Loss, in particular of medium spiny neurons in the striatum results in dysfunction of neuronal circuits controlling motor function and muscle coordination. Dysfunction and atrophy in other brain regions also occurs early in disease and leads to cognitive decline, mood disorder and dementia. Physical symptoms of Huntington's disease can can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. The earliest symptoms are a general lack of coordination and an unsteady gait. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioural and psychiatric problems. Physical abilities are gradually impeded until coordinated movement becomes very difficult, and mental abilities generally decline into dementia. About 6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly. This variant is classified as juvenile, akinetic-rigid or Westphal variant HD. Currently there are no effective therapies to halt or slow the progression of the disease. Tetrabenazine is the only approved drug for the symptomatic treatment of chorea in Huntington's disease, but has modest clinical benefit with no proven disease modifying effect. There are no approved drugs for the treatment of the cognitive deficits or mood disorders that are typical co- morbid symptoms of the disease.

Huntington's disease is caused by an autosomal dominant mutation on either of an individual's two copies of a gene called Huntingtin. The mutation in the Huntingtin gene results in an expansion of the CAG repeat in exon 1 , resulting in an extended polyglutamine repeat at the N-terminus of the protein. Repeat lengths of >35 are considered to be pathological with repeat length correlating with age of onset. The expanded polyglutamine repeat is thought to result in a toxic gain of function in the Huntingtin protein, resulting in the appearance of Huntingtin protein inclusions in numerous cells in the brain, with subsequent cell death, in particular in the striatum. While the precise mechanism of mutant Huntingtin-induced cellular toxicity is unknown, multiple lines of evidence suggest that cellular dysfunction occurs as a consequence of transcriptional dysregulation. In particular mutant Huntingtin protein has been shown to reduce the activity of a number of critical transcription factors including CREB (cAMP response element-binding protein) and PGC1 -alpha (peroxisome proliferator-activated receptor-gamma coactivator 1 alpha). Another hypothesis suggests that dysregulation of BDNF protein release from cortical neurons that project onto the medium spiny neurons of the striatum is a major factor in the sensitivity of medium spiny neurons to dysfunction and cell death in Huntington's disease. Levels of BDNF mRNA transcripts in cortex and levels of BDNF protein in the striatum are consistently reported to be decreased in human HD tissue and mouse disease models.

The present invention provides the use of a compound of formula (I): 5-{5-[(2,4- dimethyl-1 ,3-thiazol-5-yl)methyl]-1 ,3,4-oxadiazol-2-yl}-1-ethyl-/V-(tetrahydro-2/-/-pyran-4- yl)-1 H-pyrazolo[3,4-ib]pyridin-4-amine

(i) or a pharmaceutically acceptable salt thereof for the treatment of Huntington's disease.

If the compound of formula (I) is used in the salt form, the salt of the compound of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse J.Pharm.Sci (1977) 66, pp 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g. oxalates or formates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention.

The compound of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope the use of the compound of formula (I) in all possible stoichiometric and non-stoichiometric forms. The compound of formula (I) may be prepared in crystalline or non-crystalline form and, if crystalline, may optionally be solvated, eg. as the hydrate. This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (eg. water). In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. The present invention includes within its scope the use of the compound of formula (I) in any polymorphic form.

Since the invention relates to the use of the compound of formula (I) in pharmaceutical compositions it will readily be understood that the compound is preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compound may be used for preparing the more pure forms used in the pharmaceutical compositions.

The compound of formula (I) may be prepared using methods disclosed in WO04/056823 and WO201 1/107394.

The invention also provides a method for the treatment of Huntington's disease, in a subject in need thereof, comprising administering to said subject an effective amount of the compound of formula (I), or a pharmaceutically acceptable salt thereof.

The invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of Huntington's disease.

For use in therapy the compound of formula (I) is usually administered as a pharmaceutical composition.

The compound of formula (I), or its pharmaceutically acceptable salts, may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal administration, and the pharmaceutical compositions adapted accordingly.

The compound of formula (I) or its pharmaceutically acceptable salts which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges.

A liquid formulation will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier(s) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent.

A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or nonaqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluorochloro- hydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.

Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

Compositions suitable for transdermal administration include ointments, gels and patches.

In one embodiment the composition is in unit dose form such as a tablet, capsule or ampoule.

The composition may contain from 0.1 % to 100% by weight, for example from 10 to 60% by weight, of the active material, depending on the method of administration. The composition may contain from 0% to 99% by weight, for example 40% to 90% by weight, of the carrier, depending on the method of administration. The composition may contain from 0.05mg to 1000mg, for example from 1 .0mg to 500mg, of the active material, depending on the method of administration. The composition may contain from 50 mg to 1000 mg, for example from 100mg to 400mg of the carrier, 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. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 500 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks or months.

It is to be understood that as used herein any reference to treatment includes both treatment of established symptoms and prophylactic treatment. In another aspect of the present invention the compound of formula (I) its salts and/or pharmaceutical compositions may be used in combination with another therapeutically active agent.

In particular the compound of formula (I) its salts and/or pharmaceutical compositions may be used in combination with tetrabenazine and/or the following agents in the treatment of Huntington's disease: i) neuroleptic drugs; ii) drugs for extrapyramidal side effects, for example anticholinergics (such as benztropine, biperiden, procyclidine and trihexyphenidyl), antihistamines (such as diphenhydramine) and dopaminergics (such as amantadine); iii) antidepressants; iv) anxiolytics; and v) cognitive enhancers for example cholinesterase inhibitors (such as tacrine, donepezil, rivastigmine and galantamine). Neuroleptic drugs include both classical and atypical neuroleptics.

Antidepressant drugs include serotonin reuptake inhibitors (such as citalopram, escitalopram, fluoxetine, paroxetine and sertraline); dual serotonin/noradrenaline reuptake inhibitors (such as venlafaxine, duloxetine and milnacipran); Noradrenaline reuptake inhibitors (such as reboxetine); tricyclic antidepressants (such as amitriptyline, clomipramine, imipramine, maprotiline, nortriptyline and trimipramine); monoamine oxidase inhibitors (such as isocarboxazide, moclobemide, phenelzine and tranylcypromine); and others (such as bupropion, mianserin, mirtazapine, nefazodone and trazodone).

Mood stabiliser drugs include lithium, sodium valproate/valproic acid/divalproex, carbamazepine, lamotrigine, gabapentin, topiramate and tiagabine.

Anxiolytics include benzodiazepines such as alprazolam and lorazepam.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical composition and thus a pharmaceutical composition comprising a combination as defined above together with one or more pharmaceutically acceptable carriers and/or excipients represent a further aspect of the invention.

The individual compounds of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical composition(s).

The invention also provides a method of preparing a combination as defined herein, the method comprising either

(a) preparing a separate pharmaceutical composition for administration of the individual compounds of the combination either sequentially or simultaneously, or

(b) preparing a combined pharmaceutical composition for administration of the individual compounds of the combination simultaneously,

wherein the pharmaceutical composition comprises the combination together with one or more pharmaceutically acceptable carriers and/or excipients.

Figures:

Figure 1 : Effect of 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]-1 ,3,4-oxadiazol-2-yl}- 1 -ethyl-/V-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazolo[3,4-b]pyridin-4-amine (Compound I) on BDNF protein level in striatum. Group A: Vehicle-treated wild-type mice; Group B: Vehicle-treated R6/2 mice; Group C: 0.1 mg/kg Compound l-treated R6/2 mice; Group D: 1 mg/kg Compound l-treated R6/2 mice; Group E: 3 mg/kg Compound l-treated R6/2 mice; Group F: 10 mg/kg Compound l-treated R6/2 mice; Group G: 30 mg/kg Compound l-treated R6/2 mice. Data are presented as mean ± SEM.

Figure 2: A Venn diagram to illustrate 16 and 21 altered probes in common to vehicle-treated R6/2 samples and 30 mg/kg 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]- 1 ,3,4-oxadiazol-2-yl}-1-ethyl-/V-(tetrahydro-2/-/-pyran-4-yl)-1 /-/-pyrazolo[3,4-b]pyridin-4- amine (Compound I) -treated R6/2 samples, in cortex and striatum respectively. 1499 and 1 178 probes were found significantly changed in vehicle-treated R6/2 compared to vehicle-treated wild-type group, in the cortex and striatum respectively. 53 and 33 probes were found significantly changed in Compound l-treated R6/2 compared to vehicle-treated R6/2 group, in the cortex and striatum respectively.

Figure 3: The(a) 16 genes in cortex; and (b) 21 genes in striatum that were reversed in R6/2 mice following 14-day treatment of 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5- yl)methyl]-1 ,3,4-oxadiazol-2-yl}-1 -ethyl-/V-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazolo[3,4- b]pyridin-4-amine.

Example 1 : Anxiolytic effect of 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]-1 ,3,4- oxad i azo I -2 -y I }- 1 -ethy I - W-(tetra hyd ro -2 H-py ran -4-y I ) - 1 H-py razo I o [3 , 4-fe] py r i d i n -4- amine in a non-human primate model of anxiety.

The effect of 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]-1 ,3,4-oxadiazol-2-yl}-1 -ethyl-/V- (tetrahydro-2H-pyran-4-yl)-1 /-/-pyrazolo[3,4-b]pyridin-4-amine (0.03, 0.1 , 0.3, 1 or 3 mg/kg, p.o., 1 hr) on the number of postures and jumps was measured in the established marmoset human threat test (HTT), a behavioural anxiolytic test. 5-{5-[(2,4-Dimethyl-1 ,3- thiazol-5-yl)methyl]-1 ,3,4-oxadiazol-2-yl}-1-ethyl-/V-(tetrahydro-2H-pyran-4-yl)-1 H- pyrazolo[3,4-b]pyridin-4-amine significantly reduced the number of postures at 0.1 , 0.3 and 1 mg/kg without any effects on jumps indicative of an anxiolytic response without sedation. Within this anxiolytic dose range, 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]- 1 ,3,4-oxadiazol-2-yl}-1-ethyl-/V-(tetrahydro-2H-pyran-4-yl)-1 /-/-pyrazolo[3,4-b]pyridin-4- amine was well tolerated. At 3 mg/kg, the treatment was stopped due to the presence of specific side effects (ataxia, penile erection and scratching behaviour, n=1 ). No emesis was observed at any of the doses tested, suggesting a therapeutic index of at least 10 fold over emesis in this species. The first anxiolytic dose was associated with a blood exposure of 4.2ng/ml_ (Table 1 ). As it is not possible to obtain parallel PK measures from animals used in the HTT this value was extrapolated from an independent PK study from 4 marmosets whereby 1 mg/kg (p.o ) gave a blood exposure of 42.45ng/ml_ (range 12.8- 60.9ng/ml_)

Table 1 Effect of 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]-1 ,3,4-oxadiazol-2-yl}-1 -ethyl- /V-(tetrahydro-2H-pyran-4-yl)-1 H-pyrazolo[3,4-b]pyridin-4-amine (Compound I) in the marmoset human threat test Postures Jumps [Blood]

Treatment (mg/kg, p.o.) number number (ng/mL)

Vehicle 12.0±1 .0 12.712.7 -

Compound 1 | 0.03 10.7±1 .2 10.010.6 1 .3-

Vehicle 1 1 .7±0.7 13.0+1 .6 -

0.1 7.2±0.9** 10.8+2.6 4.2^a

0.3 5.3±0.4** 8.5+1 .6 12.7^a

Compound 1 1 5.5±0.6** 8.5+1 .3 42.5^a

Compound I was administered orally 60 minutes before the test (data represent means ± S.E.M.; n=5-6 animals/group; ** = p<0.01 versus vehicle group as highlighted by Dunnett's tests following significant one-way ANOVA). Data for 0.03mg/kg were from an independent experiment comparing to a matched vehicle control group as highlighted in grey. ^a = extrapolated exposures from 1 mg/kg p.o. determined in an independent PK study in marmoset (measured blood concentration = 42.45 ng/mL; range 12.8-60.9ng/mL, n=4 marmosets).

Marmoset HTT is sensitive to clinically effective anxiolytic drugs (i.e. benzodiazepines and buspirone) and antidepressants, such as the NK-i receptor antagonist casopitant which has demonstrated clinical efficacy in patients suffering from MDD. It is on this basis that it is used to predict clinical efficacy.

Example 2: Definition of a preclinical therapeutic index versus emesis

The highest non emetic dose in the ferret (1 mg/kg) was associated with a Cmax value of 85 ng/mL and an AUC value of 226 ng*h/ml_, whereas the lowest emetic dose (3 mg/kg) was associated with a Cmax value of 247 ng/mL and an AUC value of 694 ng*h/mL, suggesting a Therapeutic Index (Tl) for emesis over efficacy in the marmoset human threat test (lowest efficacious dose, 0.1 mg/kg, exposures normalised to time at T_max and PK profile over 4 hr sampling time) of≥13 fold for both Cmax and AUC.

Therapeutic indices versus emesis

The lowest active anxiolytic exposure of Compound I in the marmoset HTT test (4.2ng/mL blood at 0. 1 mg/kg, p.o.), when normalised to the PK profile of Compound I at T_max (2hrs) gave a C_max of 6.4ng/mL. This data was used to determine the absolute therapeutic indices versus the full PK profile in the ferret, with the AUC also normalised across species to the 4 hr sampling time in the ferret. T.I. = therapeutic index based on mean exposures. Example 3: Effect of 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]-1 ,3,4-oxadiazol-2- yl}-1 -ethyl-W-(tetrahydro-2H-pyran-4-yl)-1 H^yrazolo[3,4-fe]pyridin-4-amine

(Compound I) on gene expression and BDNF protein expression in R6/2 mice R6/2 (n=10) mice were treated with Compound I (0.1 , 1 , 3, 10 or 30 mg/kg) or vehicle; administered by oral gavage (10 mL/kg) twice daily (between 06:00 to 09:00 and between 18:00 and 21 :00) starting at age week 8 and continuing for 14 days. WT mice (n=10) were treated with vehicle. On day 14 the mice were dosed once more and 2 hours after the last dose the mice were sacrificed by cervical dislocation. Brains were removed and dissected into cortex and striatum. Samples were processed to purify total RNA and protein lysate.

BDNF levels in striatum were quantified using the BDNF ELISA (R&D Systems Quantikine (R) Human BDNF kit, Catelogue Number SBD00), following manufacturer's instructions. The BDNF concentrations in each sample were determined using the standard curve (ranging from 0 to 4000 pg/mL) and expressed in ng/g of tissue weight. No significant change in BDNF protein concentration in striatum was detected between vehicle-treated wild-type mice and vehicle-treated R6/2 mice. In the striatum, 1 mg/kg, 10mg/kg and 30mg/kg Compound l-treated R6/2 mice had significantly higher BDNF protein concentration, as compared to the vehicle-treated wild-type mice. Results are shown in Figure 1.

To assess the effect of Compound I on transcription in the cortex and striatum of R6/2 mice, global gene expression analysis was performed using mouse WG-6_v2 expression Bead Chip from lllumina. Samples from WT, R6/2-vehicle treated and R6/2-30 mg/kg Compound I treated mice were analysed. Principal component analysis indicates samples were clustered upon chip groups showing technical variability among samples. Batch factor was removed before T-test in order to identify differentially expressed genes either between vehicle-treated R6/2 and vehicle-treated wild-type, or between Compound l-treated R6/2 and vehicle-treated R6/2. Due to the relative small number of genes that were altered, the filtering criteria was P-value <=0.05 (not adjusted for multiple testing) and Fold Change <= 1.25 or >=-1 .25. Venn diagram was used to identify genes that were altered and common to both vehicle-treated R6/2 and Compound l-treated R6/2 (cortex and striatum) to evaluate the effects of Compound I on deficit genes in R6/2 mice.

Contrast analysis (T-test) demonstrated that 1499 and 1 178 probes were significantly changed in the cortex and striatum respectively (vehicle R6/2 verse vehicle- treated wild-type). Compared to vehicle-treated R6/2 group, 53 and 33 probes (cortex and striatum respectively) were found significantly changed in Compound l-treated R6/2 group. The cut-off was set at P < 0.05 and Fold Change > 2 or <-2. To evaluate the effects of Compound I in R6/2 mice, deficit genes in vehicle-treated R6/2 (1499 in cortex and 1 178 in striatum) and manipulated genes (53 in cortex and 33 in striatum) in Compound l-treated R6/2 were compared using Venn diagram (see Figure 2). The results showed that Compound I treatment significantly altered the expression of a subset of those genes whose expression was dysregulated in R6/2 mice (vs WT mice); 16 genes in the cortex and 21 genes in the striatum of R6/2 mice. In all cases the effect of compound treatment was to normalise gene expression in the direction toward levels measured in WT mice.

The(a) 16 genes in cortex; and (b) 21 genes in striatum that were reversed in R6/2 mice following 14-day treatment of 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]-1 ,3,4- oxadiazol-2-yl}-1-ethyl-/V-(tetrahydro-2/-/-pyran-4-yl)-1 /-/-pyrazolo[3,4-b]pyridin-4-amine are listed in Figure 3.

Claims

1. Use of a compound of formula (I): 5-{5-[(2,4-dimethyl-1 ,3-thiazol-5-yl)methyl]-

1 ,3,4-oxadiazol-2-yl}-1-ethyl-/V-(tetrahydro-2/-/-pyran-4-yl)-1 /-/-pyrazolo[3,4-b]pyridin-4- amine

2. Use of a compound of formula (I) as claimed in claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of

Huntington's disease.

3. A method for the treatment of Huntington's disease, in a subject in need thereof, comprising administering to said subject an effective amount of the compound of formula (I) as claimed in claim 1 , or a pharmaceutically acceptable salt thereof.

4. A compound of formula (I) as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, for use in the treatment of Huntington's disease.