CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National stage application of International Application No. PCT/EP2018/082450, filed Nov. 23, 2018, which claims priority to and the benefit of European Application No. 17203377.1, filed Nov. 23, 2017. These above-identified applications are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention generally relates to the treatment and/or prevention of tachycardia or tachyarrhythmia. Specifically, it relates to the use of phosphodiesterase 2 (PDE2) inhibitors in methods for the treatment and/or prevention of such conditions, in particular ventricular tachycardia.

BACKGROUND OF THE INVENTION

Cardiac arrhythmias are a group of conditions in which the heart rhythm is abnormal, either too fast or too slow. A heart rate that is too fast—typically above 100 beats per minute in an adult human—is known as “tachycardia” and one that is too slow—typically below 60 beats per minute—is known as “bradycardia”. A tachycardia which is associated with an irregularity in the normal heart rhythm may be known as a “tachyarrhythmia”. However, the terms “tachycardia” and “tachyarrhythmia” are often used interchangeably in the art and, for practical purposes, may be used by clinicians to describe any cardiac rhythm disorder associated with an increased heart rate. Although many arrhythmias are not serious, some may predispose the subject to complications such as heart failure, stroke, or cardiac arrest.

Arrhythmias arise due to abnormal impulse formation (increased automaticity and triggered activity), abnormal impulse conduction (re-entry mechanisms) and problems associated with the electrical conduction system of the heart. Arrhythmias may be categorized along two axis: slow vs fast (bradycardias vs tachycardias) and atrial vs ventricular.

Supraventricular tachycardias include atrial tachycardia, atrial fibrillation, atrial flutter and paroxysmal supraventricular tachycardia. Ventricular tachyarrhythmias include premature ventricular contractions (PVCs), ventricular fibrillation and ventricular tachycardia. Ventricular tachycardia is a type of often regular and fast heart rate that arises from improper electrical activity in the ventricles of the heart. It may occur during or after myocardial infarction, in a failing or hypertrophied heart, in cardiomyopathies, or in a structurally normal heart, and can result in cardiac arrest.

Most arrhythmias, including tachycardia, can be effectively treated using medications, medical procedures such as a pacemaker, or by surgery (e.g. ablation). Current pharmacological treatment strategies for ventricular tachyarrhythmias, for example, include agents blocking the beta-adrenergic receptor and blockers of Ca2+, Na+and K+channels. However, these agents often prove ineffective for patients having ventricular tachyarrhythmias despite optimal treatment. Optimal dosing of beta-blockers is often limited by side-effects (e.g. bradycardia, hypotension, fatigue, etc.), while Ca2+blockers are not commonly used during heart failure due to negative effects on contractility. Especially Na+blockers, but also some K+blockers, are contraindicated in patients with structural heart disease due to its pro-arrhythmic effects (Priori, S. G., et al., 2015ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: The Task Force for the Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death of the European Society of Cardiology(ESC).Endorsed by: Association for European Paediatric and Congenital Cardiology(AEPC). Eur Heart J, 2015. 36(41): 2793-867; and Al-Khatib et al., Guidelines from AHA, 2017).

Beta-blockers, such as Metoprolol, are the standard treatment for most types of tachyarrhythmias, including ventricular tachycardias. Other drugs in use for the treatment of serious (possibly fatal) abnormal heart rhythm (such as ventricular tachycardia, paroxysmal supraventricular tachycardia and atrial fibrillation) include propafenone hydrochloride (Rythmol). It is used to restore normal heart rhythm and maintain a regular, steady heartbeat. Propafenone is a Class 1C anti-arrhythmic drug with local anaesthetic effects and a direct stabilising action on myocardial membranes. Adverse side-effects associated with Rythmol occur most frequently in the gastrointestinal, cardiovascular and central nervous systems. In about 20% of patients treatment with Rythmol must be discontinued due to adverse reactions.

There thus remains a need for new drugs for the treatment or prevention of tachycardias, in particular ventricular tachycardias. We propose herein the local and selective activation of Na+/K+-ATPase (sodium potassium adenosine triphosphatase or “NKA”, also known as the Na+/K+pump or sodium-potassium pump) by the inhibition of PDE2 as a new treatment strategy for such disorders. This mechanism differs from the mechanism of conventional drugs, such as beta-blockers and Class 1 anti-arrhythmics, which are used to treat ventricular tachycardias by targeting beta-adrenergic receptors, calcium channels, Na+channels or K+channels.

PDE2 is one of a number of different phosphodiesterases (PDEs) found in mammals. The PDE family of enzymes regulates intracellular levels of the secondary messenger cyclic nucleotides cAMP and/or cGMP through hydrolytic control. These cyclic nucleotides function as intracellular signaling molecules in all mammalian cells. PDE enzymes hydrolyse cAMP and/or cGMP by breaking the phosphodiester bonds to form the corresponding monophosphates.

The different PDEs are sub-divided into 11 families (PDE1 to PDE11) based on substrate specificity, inhibitor sensitivity and, more recently, based on sequence homology. The 11 families are coded by 21 genes providing several families with multiple members. PDEs in the same family are functionally related. PDEs have different substrate specificities—some are cAMP selective hydrolases (PDE4, PDE7 and PDE8), whereas others are cGMP selective hydrolases (PDE5, PDE6 and PDE9). The others, including PDE2, are dual-substrate PDEs responsible for hydrolysis of both cAMP and cGMP.

Several PDE inhibitors, in particular PDE3, PDE4 and PDE5 inhibitors, are approved for clinical use. PDE3 inhibitors, such as Milrinone, are used in cardiovascular therapies. PDE2 shows the highest expression in the brain, but is also found in other tissues. Inhibition of PDE2 results in increased cAMP and cGMP levels that may improve cognitive function. To date, PDE2 inhibitors have mainly been documented in the literature for use in the treatment of various cognitive disorders, e.g. in neuronal development, learning and memory, in the treatment of neurological disorders, and neurodegenerative disorders such as dementia, Alzheimer's disease, etc. Several PDE2 inhibitors have undergone phase I clinical trials for cognitive disorders, including TAK-915 (Takeda), ND-7001 (Neuro3d/Evotec), and PF-05180999 (Pfizer). For example, in Mikami et al.,J. Med. Chem.,2017, 60(18): 7677-7702, oral administration of TAK-915 is shown to elevate 3′,5′-cyclic guanosine monophosphate (cGMP) levels in mouse brains and to improve cognitive performance in rats. As a result of these studies, the compound was advanced into human clinical trials.

Other documents which describe PDE2 inhibitors include EP 3026051, WO 2005/021037 and WO 2012/168817. In EP 3026051 it is suggested that the compounds have a PDE2A inhibitory activity and are useful as a prophylactic or therapeutic drug for schizophrenia, Alzheimer's disease and the like. In WO 2005/021037, known PDE2 inhibitors are combined with known pulmonary surfactants for use in the treatment of pulmonary lesions, specifically ARDS (Adult Respiratory Distress Syndrome), IRDS (Infant Respiratory Distress Syndrome), ALI (Acute Lung Injury) and Asthma bronchiale. In WO 2012/168817 various compounds are described for use as PDE2 inhibitors and/or CYP3A4 inhibitors and are proposed for use in treating central nervous system disorders, cognitive disorders, schizophrenia, and dementia. None of these documents propose the use of any PDE2 inhibitor in the treatment of any cardiac-related disorder.

PDE2 is also expressed in heart tissue and there has been some speculation, albeit unsupported, relating to the use of PDE2 inhibitors in the treatment or prevention of cardiac arrhythmias (see e.g. WO 2006/072612, WO 2004/089953, WO 2016/073424 and WO 2006/024640). WO 2004/089953 and WO 2006/024640, for example, relate to new PDE2 inhibitors which, it is postulated, may be effective in the treatment or prevention of an extremely wide range of conditions, including pneumonia, arthritis, retinal blindness, Alzheimer's disease, etc. On the basis that PDE2 is shown in myocardium, these documents propose that the compounds may have the potential to protect against “cardiac arrhythmias”, but no evidence is provided to support this. There is also nothing to suggest whether the compounds which are disclosed in these documents may be suitable for the treatment or prevention of any particular group of cardiac arrhythmias, let alone ventricular tachycardias. Against this background, it could not have been predicted that the PDE2 inhibitors would necessarily be suitable for the treatment of tachycardia as evidenced herein.

The term “cardiac arrhythmia” broadly defines a range of different cardiac rhythm disorders that require different therapeutic approaches. Both the origin (atrial vs ventricular) and type (tachyarrhythmia vs bradyarrhythmia) of arrhythmia are important to decide before initiating a therapy. Atrial arrhythmias are often treated in a completely different manner than ventricular arrhythmias. For example, adenosine and cardiac glycosides (e.g. digoxin) are used to treat various atrial arrhythmias, but could induce or exacerbate ventricular arrhythmias. Similarly, a treatment that is suitable for a tachyarrhythmia is generally contraindicated in the case of bradyarrhythmia. For example, beta-blockers such as Metoprolol are a treatment for tachyarrhythmia, but cause bradyarrhythmias. Beta-blockers (e.g. Metoprolol) are therefore contraindicated in all types of bradyarrhythmias. Treatment of arrhythmias can also depend on the underlying cause or condition. Treatment of ventricular tachyarrhythmias in heart failure or following a myocardial infarction is different from treatment of ventricular tachyarrhythmias in genetic diseases such as CPVT and long QT syndrome. For example, Flecainide (a Na+channel blocker which is a Class 1 anti-arrhythmic drug) is commonly used in CPVT and long QT syndrome, but is contraindicated in heart failure and following a myocardial infarction. Thus, depending on the origin and type, cardiac arrhythmias can be divided into different groups which require a different therapeutic approach. A general reference to the treatment of “cardiac arrhythmia” is not sufficient to suggest which type of arrhythmia might be treated.

In contrast to the prior art, the present invention relates to the treatment or prevention of tachycardias and, in particular, ventricular tachycardia. Others positively teach away from the findings presented herein. For example, Vettel, C., et al. (Phosphodiesterase2Protects Against Catecholamine-Induced Arrhythmia and Preserves Contractile Function After Myocardial Infarction. Circ Res, 2017. 120(1): 120-132) suggest that a greater PDE2 abundance protects against arrhythmias and improves contraction force after severe ischemic insult. They therefore propose activation of PDE2 as a therapeutic strategy to protect the heart from arrhythmia and contractile dysfunction. WO 2005/035505 further warns that PDE inhibitors may increase heart rate and even cause arrhythmia. This is contrary to our findings presented herein which support the use of PDE2 inhibitors in the treatment of tachycardia.

Lowered activity of NKA has been identified as an important upstream contributor to several arrhythmias (Faggioni, M. and B. C. Knollmann,Arrhythmia Protection in Hypokalemia: A Novel Role of Ca2+-Activated K+ Currents in the Ventricle. Circulation, 2015. 132(15): 1371-3), but to our knowledge no specific activators of NKA exist. The findings presented herein show that PDE2 inhibition strongly activates NKA and prevents ventricular tachyarrhythmias in mice with heart failure and inherited arrhythmia syndromes (Ankyrin+/−mice, a type of long QT syndrome, and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) mice). The ability of PDE2 inhibition to prevent arrhythmias was blunted with the addition of superAKAP, a peptide that with high specificity displaces the RII-PKA from AKAPs. Together with data showing that superAKAP abrogates the effect of PDE2 inhibition on the NKA current, this suggests that PDE2 regulates NKA and prevents ventricular tachyarrhythmias by regulating cAMP levels in a local domain.

PDE2 inhibition as an anti-arrhythmic treatment as herein described represents a novel treatment strategy in two ways: 1) as an activator of NKA; and 2) by targeting cAMP levels in discrete domains. The data presented in the accompanying examples also suggests that PDE2 is up-regulated in human hypertrophy and ageing, as we found increased expression of PDE2-mRNA in cardiomyocyte-specific nuclei. This is in line with previous data (Mehel, H., et al.,Phosphodiesterase-2is up-regulated in human failing hearts and blunts beta-adrenergic responses in cardiomyocytes. J Am Coll Cardiol, 2013. 62(17): 1596-606) and indicates that PDE2 inhibition might be a desirable anti-arrhythmic target in human chronic heart disease.

We report herein a novel treatment strategy, namely PDE2 inhibition, for the treatment and/or prevention of tachycardia, in particular ventricular tachycardia. In particular, we have found a novel regulatory mechanism of NKA in which PDE2 locally regulates NKA activity through interaction with NKA and PKA-RII. Although not wishing to be bound by theory, we suggest that this mechanism underlies the anti-arrhythmic effects seen both in vivo and in isolated ventricular myocytes in heart failure, Ankyrin B+/−mice, and in CPVT. This is supported by the finding that PDE2 inhibition reduces intracellular Ca2+loading mainly through increased Ca2+extrusion through NCX (a downstream effect of increasing NKA activity) and because the anti-arrhythmic effect in vivo is abolished with superAKAP, which disrupts local AKAP-bound PKA-RII.

SUMMARY OF THE INVENTION

The invention provides a selective PDE2 inhibitor for use in the treatment of tachycardia or tachyarrhythmia, in a subject.

The invention further provides a method of treatment of tachycardia or tachyarrhythmia, in a subject in need of such treatment, said method comprising the step of administering to said subject a therapeutically effective amount of a selective PDE2 inhibitor.

The invention further provides the use of a selective PDE2 inhibitor in the manufacture of a medicament for use in the treatment of tachycardia or tachyarrhythmia, in a subject.

The invention also provides a package comprising: (i) a selective PDE2 inhibitor or a pharmaceutical composition comprising a selective PDE2 inhibitor; and (ii) printed instructions and/or a label relating to the use of (i) in the treatment of tachycardia or tachyarrhythmia, in a subject.

The invention further provides a method of combination therapy for the treatment of tachycardia or tachyarrhythmia, in a subject in need of such treatment, said method comprising the step of administering to said subject a therapeutically effective amount of a selective PDE2 inhibitor, and simultaneously or separately (e.g. sequentially) one or more cardiovascular drugs, e.g. anti-arrhythmic drugs.

The invention also provides a pharmaceutical composition comprising a selective PDE2 inhibitor and one or more cardiovascular drugs, e.g. anti-arrhythmic drugs, optionally in combination with at least one pharmaceutically acceptable carrier or excipient.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a selective PDE2 inhibitor for use in the treatment of tachycardia or tachyarrhythmia in a subject. As defined herein, “treatment” also includes prophylactic treatment, i.e. prevention.

As used herein, the term “tachycardia” refers to an elevated heart rate, i.e. a heart rate that is too fast. Typically, this may refer to a heart rate that is above 100 beats per minute in an adult human. The term “tachyarrhythmia” refers to a tachycardia which is associated with an irregularity in the normal heart rhythm (i.e. an abnormal heart rhythm). In some cases, these terms may be used interchangeably in the art to describe any cardiac rhythm disorder associated with an increased heart rate.

The invention relates, in particular, to the treatment and/or prevention of ventricular tachycardia, e.g. treatment to prevent ventricular tachycardia. As used herein, the term “ventricular tachycardia” refers to an abnormal and very fast heart rhythm that begins in the ventricles of the heart and which is caused by a malfunction in the heart's electrical system. More specifically, it refers to a pulse of more than 100 beats per minute with at least three consecutive abnormal heartbeats in a row originating from the ventricles.

In an embodiment, the invention relates to the treatment or prevention of ventricular tachycardia with reduced side-effects. Reduced side-effects include, but are not limited to, a reduction in one or more of the following adverse events: fatigue, dizziness, reduced exercise tolerance, bradycardia, nausea, diarrhea, worsening of heart failure, headache, pulmonary toxicity (interstitial pneumonitis, acute respiratory distress syndrome, diffuse alveolar hemorrhage), thyroid dysfunction, hepatotoxicity, ocular changes, and QT prolongation.

The compounds for use in the invention are selective inhibitors of PDE2, preferably selective inhibitors of human PDE2, as herein defined. An “inhibitor of PDE2” is any compound having an effect to block the degradative action of phosphodiesterase 2 (PDE2). An “inhibitor of human PDE2” should be construed accordingly. In one embodiment, the compounds for use in the invention are selective inhibitors of PDE2A, e.g. selective inhibitors of human PDE2A.

As used herein, the term “selective PDE 2 inhibitor” refers to a compound which selectively inhibits PDE2 over other PDE types, i.e. which inhibits PDE2 more strongly than other PDE types and particularly one or more of the following: PDE1, PDE3, PDE4, PDES and PDE10. In particular, the compound may inhibit PDE2 more strongly than it inhibits PDE10. More particularly, the compound may inhibit PDE2 more strongly than it inhibits all other PDE types.

Compounds which are preferred for use in the invention are those which are a selective human PDE2 inhibitor, i.e. which selectively inhibit human PDE2 over other human PDE types, e.g. compounds which inhibit human PDE2 more strongly than one or more of the following: human PDE1, human PDE3, human PDE4, human PDE5 and human PDE10. In particular, the compound may inhibit human PDE2 more strongly than it inhibits human PDE10. More particularly, the compound may inhibit human PDE2 more strongly than it inhibits all other human PDE types.

A PDE2 inhibitor for use in the invention may have a selectivity for inhibiting the activity of PDE2 (e.g. human PDE2) which is at least 10-fold compared to at least one other PDE type (e.g. human PDE type), preferably compared to PDE10 (e.g. human PDE10), e.g. compared to all other PDE types (e.g. all other human PDE types). In some embodiments, the degree of selectivity (e.g. compared to all other PDE types or all other human PDE types) will be at least 20-fold, e.g. at least 30-fold, or at least 50-fold. In other embodiments, the degree of selectivity (e.g. compared to all other PDE types or all other human PDE types) may be at least 100-fold, at least 200-fold, at least 300-fold, at least 400-fold, at least 500-fold, or at least 1000-fold.

Inhibitors of the activity of PDE2 for use in the invention will typically inhibit PDE2, e.g. human PDE2, with an IC50value (the concentration which produces 50% inhibition of substrate hydrolysis) of less than about 100 nM, preferably less than about 50 nM, e.g. less than about 40 nM, less than about 30 nM, less than about 20 nM or less than about 10 nM. In some embodiments, the compounds may inhibit PDE2, e.g. human PDE2, with an IC50value of less than 5 nM, or less than 1 nM. Methods for the measurement of PDE activity and for the determination of IC50values are well known and described in the art, for example, in Weeks et al., Int. J. Impot. Res. 17:5-9, 2005, and Souness et al., British Journal of Pharmacology 118: 649-658, 1996, the entire contents of which are incorporated herein by reference.

A wide range of PDE2 inhibitors are known and described in the literature and in earlier patent publications, together with methods for their manufacture. Any compound having the desired PDE2 inhibitory activity may be used in the invention and such compounds may readily be determined, for example using PDE inhibition and selectivity assays well known in the art, such as those described in any of the following publications, the entire contents of which are incorporated herein by reference: Boess et al. (Neuropharmacology 47:1081-1092, 2004); Maehara et al. (European Journal of Pharmacology 811: 110-116, 2017); Gomez et al. (J. Med. Chem. 60: 2037-2051, 2017); and Rombouts et al. (ACS Med. Chem. Lett. 6: 282-286, 2015).

Examples of PDE2 inhibitors suitable for use in the invention include those described in any of the following documents, the entire contents of which are incorporated herein by reference: Trabanco et al.,Towards selective phosphodiesterase2A(PDE2A)inhibitors: a patent review(2010-present), Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016; WO 2002/050078 (Bayer); WO 2004/089953 (Altana Pharma AG); WO 2006/024640 (Altana Pharma AG); WO 2006/072612 (Altana Pharma AG); WO 2006/072615 (Altana Pharma AG); WO 2004/41258 (Neuro3d); EP 1548011 (Neuro3d); EP 1749824 (Neuro3d); WO 2005/041957 (Pfizer Products Inc.); WO 2005/061497 (Pfizer Products Inc.); WO 2010/054253 (Biotie Therapies GmbH and Wyeth); WO 2012/104293 (Boehringer Ingelheim International GmbH); WO 2014/019979 (Boehringer Ingelheim International GmbH); WO 2013/000924 (Janssen Pharmaceutica NV); US 2012/0214791 (Pfizer); WO 2012/168817 (Pfizer); WO 2014/010732 (Takeda); EP 3 026 051 (Takeda); WO 2005/021037 (Pfizer); Mikami et al., J. Med. Chem. 60: 7677-7702, 2017; Mikami et al., Chem. Pharm. Bull. 65(11): 1058-1077, 2017; Masood et al., JPET 331(2): 690-699, 2009; Gomez et al., Bioorg. Med. Chem. Lett. 23: 6522-6527, 2013; Maehara et al., European Journal of Pharmacology 811: 110-116, 2017; Gomez et al., J. Med. Chem. 60: 2037-2051, 2017; Rombouts et al., ACS Med. Chem. Lett. 6: 282-286, 2015; Redrobe et al., Psychopharmacology 231: 3151-3167, 2014; and Buijnsters et al., ACS Med. Chem. Lett. 5:1049-1053, 2014. Pharmaceutically acceptable salts, or prodrugs of any such compounds may also be used.

Specific examples of selective PDE2 inhibitors for use in the invention include the following compounds, their pharmaceutically acceptable salts and prodrugs:

PDE2A IC50orSelectivityCompoundNameKi values *Data *BAY 60-7550 2-(3,4- dimethoxybenzyl)-7- [(2R,3R)-2-hydroxy- 6-phenylhexan-3-yl]- 5-methylimidazo[5,1- f][1,2,4]triazin-4(3H)- oneIC50= 4.7 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)>50 fold selectivity vs other PDEsIC50= 6 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)IC50= 3.3 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)IC50= 7.12 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)PDE10 IC50= 282 nMIC50= 4.12 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)PDE10 IC50> 500 nMIC50= 3 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)PDE10 IC50> 1000 nMIC50= 5 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)PDE10 IC50= 1488 nMIC50= 12 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)PDE10 IC50= 2403 nMIC50= 8 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)PDE10 IC50= 1622 nMIC50= 10 nM (Buijnsters et al., ACS Med. Chem. Lett. 5: 1049-1053, 2014)rPDE10 IC50= 4183 nM >210-fold selectivity vs all PDEsIC50= 0.29 nM (calculated from pIC50values in Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)PDE10 IC50= 21 nMIC50= 15 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)Lu AF64280Ki = 20 nM (Redrobe et al., Psycho- pharmacology 231: 3151- 3167, 2014)PDE10 Ki = 1800 nMPF-05180999IC50= 1.61 nM (U.S. 2012/ 0214791; Gomez et al., J. Med. Chem. 60: 2037- 2051, 2017)PDE selectivity: 2000x vs PDE10AIC50= 2.30 nM (Trabanco et al., Expert Opinion on Therapeutic Patents, 26(8): 933-946, 2016)>500-fold selective over other members of the PDE familyTAK-915 N-((1S)-1-(3-fluoro-4- (trifluoromethoxy) phenyl)-2- methoxyethyl)-7- methoxy-2-oxo-2,3- dihydropyrido[2,3-b] pyrazine-4-(1H)- carboxamideIC50= 0.61 nM (Mikami et at., J. Med. Chem. 60: 7677- 7702, 2017)PDE selectivity: 4100 x (vs PDE1A)N-(1S)-2-hydroxy-2- methyl-1-(4- (trifluoromethoxy)- phenyl)propyl)-5-(1H- pyrazol-1-yl) pyrazolo[1,5-a] pyrimidine-3- carboxamideIC50= 5.4 nM (Mikami et al., Chem. Pharm. Bull. 65(11): 1058-1077, 2017)630-fold selectivity vs other PDEsN-(1S)-2-hydroxy-2- methyl-1-(4- (trifluoromethoxy)- phenyl)propyl)-5-(4- methyl-1H-1,2,3- triazol-1- yl)pyrazolo[1,5-a] pyrimidine-3- carboxamideIC50= 5.4 nM (Mikami et al., Chem. Pharm. Bull. 65(11): 1058-1077, 2017)690-fold selectivity vs other PDEsN-(1S)-2-hydroxy-2- methyl-1-(4- (trifluoromethoxy)- phenyl)propyl)-5-(3- methyl-1H-1,2,4- triazol-1-yl)pyrazolo [1,5-a]pyrimidine-3- carboxamideIC50= 11 nM (Mikami et al., Chem. Pharm. Bull. 65(11): 1058-1077, 2017)610-fold selectivity vs other PDEsIC50= 5.1 nM (Mikami et al., Chem. Pharm. Bull. 65(11): 1058-1077, 2017)IC50= 24 nM (Mikami et al., Chem. Pharm. Bull. 65(11): 1058-1077, 2017)ND-7001 3-(8-methoxy-1- methyl-2-oxo-7- phenyl-2,3-dihydro- 1H-benzo[e]- [1,4]diazepin-5-yl) benzamideKi = 114 nM (Masood et al., JPET 331(2): 690-699, 2009)PDM-631 ((S)-3-cyclopropyl-6- methyl-1-(1-(4- (trifluoromethoxy) phenyl)propan-2-yl)- 1,5-dihydro-4H- pyrazolo[3,4-d] pyrimidin-4-oneIC50= 1.5 nM (Maehara et al., European Journal of Pharmacology 811: 110-116, 2017)>2000-fold selectivity vs other PDEs (less than 10% inhibition at 1 μM)DNS-8254 (5S)-1-[(3-bromo-4- fluorophenyl) carbonyl]-3,3- difluoro-5-{5-methyl- [1,2,4]triazolo[1,5-a] pyrimidin-7-yl} piperidineIC50= 8 nM (Gomez et al., J. Med. Chem. 60: 2037- 2051, 2017)PDE10A IC50= 1700 nM1-[2,3-dihydro-1- benzofuran-5- yl)carbonyl]-3-{5- methyl-[1,2,4]- triazolo[1,5-a] pyrimidin-7-yl} piperidineIC50= 3 nM (Gomez et al., J. Med. Chem. 60: 2037- 2051, 2017)6-[(3-{5-methyl- [1,2,4]triazolo[1,5- a]pyrimidin-7- yl}piperidin-1-yl) carbonyl]quinoloneIC50= 2 nM (Gomez et al., J. Med. Chem. 60: 2037- 2051, 2017)IC50= 4.2 nM (U.S. Pat. 7,851,472)hPDE2A IC50= 29 nM (Rombouts et al., ACS Med. Chem. Lett. 6: 282-286, 2015)rPDE10 IC50= 480 nMhPDE2A IC50= 3 nM (Rombouts et al., ACS Med. Chem. Lett. 6: 282-286, 2015)rPDE10 IC50= 2450 nMhPDE2A IC50= 54 nM (Rombouts et al., ACS Med. Chem. Lett. 6: 282-286, 2015)rPDE10 IC50= 3800 nMEHNA (erythro-9-(2- hydroxy-3- nonyl)adenine)* values taken from the listed publications

Preferred for use in the invention are the following selective PDE2 inhibitors: TAK-915, ND-7001, PF-05180999, Lu AF64280, and their pharmaceutically acceptable salts or prodrugs. Particularly preferred for use in the invention are PF-05180999, TAK-915, their pharmaceutically acceptable salts and prodrugs thereof.

The PDE inhibitory activity of such compounds may be tested by methods known in the art, including those described in any of the following, the entire contents of which are incorporated herein by reference: Boess et al., Neuropharmacology 47:1081-1092, 2004; Maehara et al., European Journal of Pharmacology 811: 110-116, 2017; Gomez et al., J. Med. Chem. 60: 2037-2051, 2017; Rombouts et al., ACS Med. Chem. Lett. 6: 282-286, 2015; and Redrobe et al., Psychopharmacology 231: 3151-3167, 2014. Determination of the specificity of a compound to various PDEs may involve an assay to isolate specific PDE families, to measure PDE activity in terms of cGMP/cAMP degradation, and to test the extent to which the compound in question inhibits the activity.

Any of the PDE2 inhibitor compounds herein described may be used in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” as used herein refers to any pharmaceutically acceptable organic or inorganic salt of any of the compounds herein described. A pharmaceutically acceptable salt may include one or more additional molecules such as counter-ions. The counter-ions may be any organic or inorganic group which stabilises the charge on the parent compound.

If the PDE2 inhibitor compound for use in the invention is a base, a suitable pharmaceutically acceptable salt may be prepared by reaction of the free base with an organic or inorganic acid. Non-limiting examples of acids which may be used for this purpose include hydrochloric acid, hydrobromic acid, sulfuric acid, sulfonic acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, acetic acid, trifluoroacetic acid and ascorbic acid. If the PDE2 inhibitor compound for use in the invention is an acid, a suitable pharmaceutically acceptable salt may be prepared by reaction of the free acid with an organic or inorganic base. Non-limiting examples of bases which may be suitable for this purpose include alkali and alkaline earth metal hydroxides, e.g. sodium hydroxide, potassium hydroxide or cesium hydroxide, ammonia and organic amines such as diethylamine, triethylamine, ethanolamine, diethanolamine, cyclohexylamine and dicyclohexylamine. Procedures for salt formation are conventional in the art.

Examples of suitable salts include the hydrochloride salt, hydrobromide salt, sulphate salt, phosphate salt, nitrate salt and salts with sulphonic acids, e.g. methane sulphonic acid. Other suitable salts include organic salts such as acetate, citrate and fumarate.

Any of the PDE2 inhibitor compounds herein described may alternatively be provided in the form of a prodrug. The term “prodrug” refers to a derivative of an active compound which undergoes a transformation under the conditions of use, for example within the body, to release an active drug. A prodrug may, but need not necessarily, be pharmacologically inactive until converted into the active drug. As used herein, the term “prodrug” extends to any compound which under physiological conditions is converted into any of the active PDE2 inhibitor compounds herein described. Suitable prodrugs include compounds which are hydrolyzed under physiological conditions to the desired PDE2 inhibitor.

Prodrugs may typically be obtained by masking one or more functional groups in the parent molecule which are considered to be, at least in part, required for activity using a progroup. By “progroup” as used herein is meant a group which is used to mask a functional group within an active drug and which undergoes a transformation, such as cleavage, under the specified conditions of use (e.g. administration to the body) to release a functional group and hence provide the active drug. Progroups are typically linked to the functional group of the active drug via a bond or bonds that are cleavable under the conditions of use, e.g. in vivo. Cleavage of the progroup may occur spontaneously under the conditions of use, for example by way of hydrolysis, or it may be catalyzed or induced by other physical or chemical means, e.g. by an enzyme, by exposure to a change in temperature, or to a change in pH, etc. Where cleavage is induced by other physical or chemical means, these may be endogenous to the conditions of use, for example pH conditions at the target site, or these may be supplied exogenously.

A wide variety of progroups suitable for masking functional groups in active compounds to provide prodrugs are well known in the art. For example, a hydroxy functional group may be masked as an ester, a phosphate ester, or a sulfonate ester which may be hydrolyzed in vivo to provide the parent hydroxy group. An amide functional group may be hydrolyzed in vivo to provide the parent amino group. A carboxyl group may be masked as an ester or amide which may be hydrolyzed in vivo to provide the parent carboxyl group. Other examples of suitable progroups will be apparent to those of skill in the art. The precise nature of the progroup may be selected according to need, for example depending on the desired oil or water solubility of the prodrug, its intended mode of administration and/or its intended mode of metabolism at the target site to produce the active drug compound. The progroup may, for example, be hydrophilic or lipophilic in order to increase or decrease water solubility as required. The choice of progroup may also impart other desirable properties such as enhanced absorption from the gastrointestinal tract, improved drug stability, etc.

The PDE2 inhibitors herein described are suitable for use in the treatment of tachycardia or tachyarrhythmia. For example, these may be used in the treatment of any of the following disorders: atrial tachycardia, atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, premature ventricular contractions (PVCs), ventricular fibrillation and ventricular tachycardia. In a preferred embodiment, the compounds may be used in the treatment of ventricular tachycardia. The treatment of conditions associated with an arrhythmia forms a preferred aspect of the invention, for example tachyarrhythmia.

In one embodiment, the compounds herein described may thus be used in the treatment or prevention of any of the following conditions: atrial tachycardia, atrial fibrillation, atrial flutter, paroxysmal supraventricular tachycardia, premature ventricular contractions (PVCs), ventricular fibrillation and ventricular tachycardia, for example in the treatment or prevention of any such conditions associated with an arrhythmia.

In one embodiment, the PDE2 inhibitors described herein are intended for the treatment or prevention or ventricular tachycardia. Treatment of a subject to prevent ventricular tachycardia is a preferred embodiment of the invention. Suitable subjects (e.g. patients) for treatment include subjects diagnosed as susceptible to ventricular tachycardia, and subjects who have previously experienced at least one incidence of ventricular tachycardia and who are therefore susceptible to further attacks. Treatment of such subjects is intended to reduce, preferably to eliminate, the occurrence of further ventricular tachycardiac events.

Tachycardias or tachyarrhythmias (for example, ventricular tachycardia) may be acquired, or they may be congenital. For example, they may be associated with, or arise from, various disorders relating to the heart, including but not limited to any of the following: congenital heart failure, hypertension, a myocardial infarction (either during or following a myocardial infarction), congestive heart failure, reperfusion injury or damage, ischemia, angina, dilated cardiomyopathy, post infarction heart failure, atherosclerotic peripheral arterial disease, diabetes, hypertrophic cardiomyopathy, myocarditis, channelopathies (e.g. long QT syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT) or Brugada syndrome), restrictive cardiomyopathy, infiltrative cardiac disease (e.g. amyloidosis) and alveolar hypoxia leading to pulmonary hypertension and right ventricle failure.

As used herein, the terms “treatment”, “treating” and “treat” include both therapeutic and preventative methods directed to the defined disease or disorder in a subject. Specifically, these include: (i) prevention of the disorder from occurring, or reduction of the risk that the disorder may occur, in particular when the subject may be predisposed to the disorder but has not yet been diagnosed as having it; (ii) inhibiting the disorder, in particular arresting its further development (progression) or delaying its onset; and (iii) relieving the disorder, in particular causing the regression of the disorder until a desired outcome is reached.

Subjects (e.g. patients) which may benefit from the treatment methods according to the invention include, but are not limited to, any of the following: subjects who have previously suffered a myocardial infarction; subjects who have heart failure; and subjects who may be predisposed to any of the tachycardia conditions herein described, e.g. subjects having a genetic predisposition to such conditions, e.g. to catecholaminergic polymorphic ventricular tachycardia (CPVT) in which an abnormally fast and irregular heartbeat (tachycardia) is triggered in response to physical activity or emotional stress. Subjects suffering from any of the following conditions, or who may be predisposed to any of the following conditions, are particularly suited to treatment according to the methods herein described: heart failure, post-myocardial infarction, myocarditis, hypertrophic cardiomyopathy, CPVT, long QT syndrome and Brugada syndrome. A preferred group of subjects (e.g. patients) which may be treated in accordance with the invention include those suffering from, or at risk from, heart failure, CPVT or long QT syndrome.

In an embodiment, the invention relates to the treatment and/or prevention of ventricular tachycardia in subjects (e.g. human patients) suffering from any of the following conditions, or who may be predisposed to any of the following conditions: heart failure, post-myocardial infarction, myocarditis, hypertrophic cardiomyopathy, CPVT, long QT syndrome and Brugada syndrome.

CPVT and long QT syndrome are genetic syndromes with high risk of ventricular tachycardia. Nearly all patients with these conditions currently receive some form of anti-arrhythmic treatment. Although heart failure encompasses a diverse range of conditions, there can often be an associated risk of ventricular tachycardia. In particular, the invention relates to the treatment and/or prevention of ventricular tachycardia in subjects suffering from, or at risk from, heart failure, CPVT or long QT syndrome.

Subjects who may be predisposed to tachycardia (e.g. ventricular tachycardia) include those who have previously been diagnosed and/or treated for cardiac arrhythmias (e.g. ventricular tachycardias), for example subjects who have been prescribed anti-arrhythmic drugs such as beta-blockers to manage an abnormal heart rhythm, or subjects who have an implanted cardiac defibrillator (ICD). Symptomatic heart failure patients who have an ICD may particularly benefit from the treatment methods herein disclosed.

ICDs are typically implanted in patients having a high risk of ventricular tachycardia and/or sudden cardiac death, for example patients with heart failure or long QT syndrome. Within 1 to 3 years of implantation of the device, 20-35% of patients will experience an appropriate shock, i.e. the ICD converts a potentially lethal ventricular tachycardia to a normal heart rhythm. However, a third of patients may also experience an inappropriate shock, i.e. the ICD gives an unnecessary shock. Whenever the ICD shocks, this is associated with a 2-5 fold increase in mortality due to reduced heart function. It is therefore important to be able to reduce the amount of inappropriate ICD shocks to which a patient may be subjected. This can be achieved by the use of effective medication to treat or prevent the underlying heart condition, e.g. ventricular tachycardia. In one embodiment, the methods herein described may thus be used to treat or prevent ventricular tachycardia in patients having an implanted ICD and, in particular, to reduce or minimise the number of inappropriate ICD shocks to which the patient may be subjected.

Subjects undergoing long term treatment for a cardiac arrhythmia such as ventricular tachycardia (e.g. those who have been prescribed beta-blockers for at least 6 months, or at least 12 months) may particularly benefit from the treatment methods herein described. Although beta-blockers may typically be the first line treatment for ventricular tachycardias, their efficacy varies between conditions and in different patients. The methods herein described find particular use in the treatment of patients for whom conventional treatments (e.g. treatment with beta-blockers) is not sufficient to treat cardiac arrhythmias (especially ventricular tachycardias), or in cases where conventional drugs (e.g. beta-blockers) are either contraindicated (e.g. AV block) or not tolerated by the subject.

In one embodiment, the treatment methods may be used to treat patients with ICDs in order to minimise VA-induced symptoms and/or to reduce inappropriate ICD shocks (which is particularly common in CPVT, for example).

In one embodiment, the treatment methods may be used to treat patients with ICDs who are also undergoing conventional treatment for a cardiac arrhythmia, such as ventricular tachycardia. Such patients include those having an ICD and who are undergoing treatment with a beta-blocker (e.g. those who have been prescribed beta-blockers for at least 6 months, or at least 12 months).

As used herein, a “therapeutically effective amount” relates to an amount that will lead to the desired pharmacological and/or therapeutic effect, i.e. an amount of the PDE2 inhibitor which is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of the active agent is within the capability of one skilled in the art. Generally, the dosage regimen for treating a disease or condition with any of the compounds described herein is selected in accordance with a variety of factors including the nature of the medical condition and its severity.

As used herein, “subject” will typically be a mammal. The term “mammal” includes, for example, dogs, cats, cows, sheep, horses and humans. Preferably the subject will be a human.

The PDE2 inhibitors herein described will typically be administered in the form of a pharmaceutical composition. Pharmaceutical compositions may be formulated in conventional manner using readily available ingredients. Thus, the PDE2 inhibitor may be incorporated with one or more conventional carriers, diluents and/or excipients, to produce a pharmaceutical composition such as conventional galenic preparations such as tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions (as injection or infusion fluids), emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, sterile packaged powders, etc.

Suitable excipients, carriers or diluents are lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, calcium carbonate, calcium lactose, corn starch, aglinates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, water, water/ethanol, water/glycol, water/polyethylene, glycol, propylene glycol, methyl cellulose, methylhydroxybenzoates, propyl hydroxybenzoates, talc, magnesium stearate, mineral oil or fatty substances such as hard fat or suitable mixtures thereof. Agents for obtaining sustained release formulations, such as carboxypolymethylene, carboxymethyl cellulose, cellulose acetate phthalate, or polyvinylacetate may also be used. The compositions may additionally include lubricating agents, wetting agents, viscosity increasing agents, colouring agents, granulating agents, disintegrating agents, binding agents, osmotic active agents, emulsifying agents, suspending agents, preserving agents, sweetening agents, flavouring agents, adsorption enhancers, e.g. for nasal delivery (bile salts, lecithins, surfactants, fatty acids, chelators) and the like. The pharmaceutical compositions may be formulated so as to provide quick, sustained or delayed release of the PDE2 inhibitor after administration to the patient by employing procedures well known in the art.

The active ingredient (i.e. the PDE2 inhibitor) in such compositions may comprise from about 0.01% to about 99% by weight of the formulation, preferably from about 0.1 to about 50%, for example 10% by weight.

The administration may be by any suitable method known in the medicinal arts, including for example oral, parenteral (e.g. intramuscular, subcutaneous, intraperitoneal or intravenous), percutaneous, buccal, rectal or topical administration, or administration by inhalation. The preferred routes of administration are oral and parenteral (e.g. intravenous or intraperitoneal). Preferred formulations for use in the invention are thus tablets, capsules or intravenous solutions.

Tablets are typically prepared by direct compression or a granulation procedure, for example using standard fluid bed technology. The tablets are preferably coated with a film coating or another coating such as an enteric coating. The capsules are preferably gelatine capsules. A composition for injection can be a ready to use solution or a dry material to be dissolved before administration. All intravenous compositions are sterile. Any sterilisation method may be used, such as heat sterilisation and aseptic preparation.

The unit dose will vary depending upon the chosen PDE2 inhibitor and the disease or disorder being treated. Typically, the unit dose will vary from 0.1 mg to 500 mg; more preferably from 1 mg to 300 mg. A typical daily dose may be from 0.1 mg to 2 grams, more preferably 1 mg to 1 g, e.g. 1 mg to 600 mg.

Typical daily doses per kg body weight of the subject may vary from 0.01 mg/kg to 50 mg/kg, preferably from 0.1 mg/kg to 40 mg/kg, e.g. from 1 mg/kg to 20 mg/kg or from 5 mg/kg to 10 mg/kg.

The dosing regime will vary depending upon the clinical situation. Typical average dosing will be once, twice or three times a day, preferably once or twice a day.

The precise dosage of the active compound to be administered and the length of the course of treatment will be dependent on a number of factors including for example, the age and weight of the subject, the specific condition requiring treatment and its severity, and the route of administration. Suitable dosages can readily be determined by those of skill in the art.

PDE2 inhibition as an anti-arrhythmia treatment as herein described may be used alone, for example where this is more effective than known treatment options (e.g. treatment with beta-blockers) and/or where current treatments are not relevant, for example where these may be contraindicated in any given patient group. Alternatively, any of the methods of treatment herein described may advantageously be combined with administration of one or more additional active agents which are effective in treating the disorder or disease to be treated, i.e. as an add-on therapy to current regimes). Such treatment methods may involve simultaneous, separate or sequential administration of the PDE2 inhibitor, or a pharmaceutical composition containing the PDE2 inhibitor, and the additional active agent. Where the actives are to be administered simultaneously, these may be provided in the form of a combined preparation. Thus, the pharmaceutical compositions herein described may additionally contain one or more of such active agents.

Other active agents which may be co-administered with the PDE2 inhibitor may include cardiovascular drugs. For example, the PDE2 inhibitor may be co-administered with one or more drugs that treat hypertension, heart failure, arrhythmia and/or post infarction myocardial reperfusion syndrome. Examples of such drugs include beta-blockers, calcium antagonists, ACE-inhibitors, ATII/-blockers and anti-arrhythmic drugs. In one embodiment, the cardiovascular drug may be a beta-blocker, for example a β1-selective beta-blocker such as acebutolol, atenolol, betaxolol, bisoprolol, celiprolol, metoprolol, nebivolol or esmolol. In a particular embodiment, metoprolol may be co-administered with a PDE2 inhibitor in the treatment or prevention of any of the conditions herein described, in particular in the treatment or prevention of ventricular tachycardia.

