WO2010114563A1 - Metabolites of k201 (jtv-519) (4- [3-{1- (4- benzyl) piperidinyl} propionyl] -7 -methoxy 2, 3, 4, 5-tetrahydro-1,4-benzothiazepine monohydrochloride - Google Patents

Abstract

Disclosed herein are methods of treating or preventing cardiac rhythm disorders with metabolites of -[3-(4-benzylpiperidin-1-yl)propionyl]-7methoxy-2, 3, 4, 5-tetrahydro-1, 4- benzothiazepine monohydrochloride). Also disclosed are uses of metabolites of -[3-(4- benzylpiperidin-1 -yl)propionyl]-7methoxy-2, 3, 4, 5-tetrahydro-1, 4-benzothiazepine monohydrochloride) in the treatment of cardiac disorders, and in the manufacture of medicaments for the treatment or prevention of cardiac disorders, such as cardiac rhythm disorders.

Description

SQUEL.004VPC PATENT

METABOLITES OF K201 (JTV-519) (4-[3-{l-(4-

BENZYL)PIPERIDINYLJPROPIONYL]-T-METHOXY 2, 3, 4, 5-TETRAHYDRO-l,4- BENZOTHIAZEPINE MONOHYDROCHLORIDE)

BACKGROUND OF THE INVENTION Field of the Invention

[0001] Embodiments disclosed herein relate to the field of cardiac therapeutics. In particular, disclosed herein are compositions and methods for treating various cardiac-related conditions. Description of the Related Art

[0002] Cardiac disorders are the leading causes of death in the United States, and are common costly, often disabling and deadly conditions. Primarily due to costs of hospitalization, cardiac disorders are associated with high health expenditures, totaling more than $35 billion in the United States alone.

[0003] Many cardiac disorders are inter-related, including cardiac rhythm disorders, sudden cardiac death, heart failure, acute coronary syndrome, hypertension, pulmonary edema, and chronic obstructive pulmonary disease.

[0004] Currently available treatments for cardiac disorders, such as antiarrhythmics, are fraught with problems. Atrial flutter and/or atrial fibrillation (AF) are the most commonly sustained cardiac arrhythmias in clinical practice, and are likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States. While AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class I and Class III antiarrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects, including ventricular proarrhythmia. Ventricular rhythm disorders, such as ventricular fibrillation (VF), are the most common cause associated with acute myocardial infarction, ischemic coronary artery disease and congestive heart failure. [0005] Although various therapeutic agents for cardiac disorders are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been approved. For example, antiarrhythmic agents of Class I, according to the classification scheme of Vaughan- Williams ("Classification of antiarrhythmic drugs," Cardiac Arrhythmias, edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra, Sodertalje, pp 449-472 (1981)), which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (V_max) are inadequate for preventing cardiac disorders such as ventricular fibrillation because they shorten the wave length of the cardiac action potential, thereby favoring re-entry. In addition, they have problems regarding safety, as they depress myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of impulse conduction. The serious adverse side effects resulted in the termination of the CAST (coronary artery suppression trial) study, because the Class 1 antagonists had a higher mortality than placebo controls. Class II and Class IV antiarrhythmics, while having a higher safety margin than the Class I agents, are also of limited therapeutic value. In particular, β-adrenergenic receptor blockers and calcium channel (le_a) antagonists, which belong to Class II and Class IV, respectively, are also of limited therapeutic values, as their therapeutic effects is are limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease.

[0006] Class III antiarrhythmic agents function by increasing myocardial refractoriness via a selective prolongation of cardiac action potential duration (APD). Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e., Na⁺ or Ca²⁺ currents; hereinafter I_N8 and Ic_a, respectively) or by reducing outward repolarizing potassium K⁺ currents. The delayed rectifier (I_K) K⁺ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (I_t0) and inward rectifier (Iκi) K⁺ currents are responsible for the rapid initial and terminal phases of repolarization, respectively. Cellular electrophysiologic studies have demonstrated that I_K consists of two pharmacologically and kinetically distinct K⁺ current subtypes, Iκ_r (rapidly activating and deactivating) and I_KS (slowly activating and deactivating). (Sanguinetti and Jurkiewicz, "Two components of cardiac delayed rectifier K⁺ current. Differential sensitivity to block by Class III antiarrhythmic agents", J Gen. Physiol 96:195-215 (1990)). Iic_r is the product of the human ether-a-go-go gene (hERG). Expression of hERG cDNA in cell lines leads to production of a hERG current which is almost identical to Iκ_r (Curran et al., "A molecular basis for cardiac arrhythmia: hERG mutations cause long QT syndrome," Cell 80(5):795-803 (1995)).

[0007] With the exception of amiodarone, which is a blocker of I_KS, Class III antiarrhythmic agents including d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide-N-[l '-6-cyano-l ,2,3,4-tetrahydro-2-naphthalenyl)-3,4-dihydro-4- hydroxyspiro[2H-l-benzopyran-2,4'-piperidin]-6-yl], (+)-, monochloride A-499) predominantly, if not exclusively, block Iκ._r. Amiodarone also blocks I_N3 and Ic₃, effects thyroid function, is as a nonspecific adrenergic blocker, acts as an inhibitor of the enzyme phospholipase, and causes pulmonary fibrosis (Nademanee, K "The Amiodarone Odessey". J. Am. Coll. Cardiol. 20: 1063- 1065 (1992)).

[0008] Since I_Kr blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias-like AF and VF. These agents have a liability, however, in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, Torsade des Pointes, a specific type of polymorphic ventricular tachycardia which is commonly associated with excessive prolongation of the electrocardigraphic QT interval, hence termed "acquired long QT syndrome", has been observed when these compounds are utilized (Roden, D. M. "Current Status of Class III Antiarrhythmic Drug Therapy", Am J. Cardiol, 72:44B-49B (1993)). The exaggerated effect at slow heart rates has been termed "reverse frequency-dependence" and is in contrast to frequency-independent or frequency-dependent actions.

[0009] The slowly activating component of the delayed rectifier (Iκ_s) potentially overcomes some of the limitations of Iκ_r blockers associated with ventricular arrhythmias. Because of its slow activation kinetics, however, the role of Iκ_s in atrial repolarization may be limited due to the relatively short APD of the atrium. Consequently, although I_Ks blockers may provide distinct advantage in the case of ventricular arrhythmias, their ability to affect supraventricular tachyarrhythmias (SVT) is considered to be minimal.

[0010] Another major defect or limitation of most currently available Class III antiarrhythmic agents is that their effect increases or becomes more manifest at or during bradycardia or slow heart rates, and this contributes to their potential for proarrhythmia. On the other hand, during tachycardia or the conditions for which these agents or drugs are intended and most needed, they lose most of their effect. This loss or diminishment of effect at fast heart rates has been termed "reverse use-dependence" (Hondeghem and Snyders, "Class III antiarrhythmic agents have a lot of potential but a long way to go: Reduced effectiveness and dangers of reverse use dependence", Circulation 81 :686-690 (1990); Sadanaga et al., "Clinical evaluation of the use- dependent QRS prolongation and the reverse use-dependent QT prolongation of class III antiarrhythmic agents and their value in predicting efficiency" Amer. Heart Journal 126: 114-121 (1993)), or "reverse rate-dependence" (Bretano, "Rate dependence of class III actions in the heart", Fundam. Clin. Pharmacol. 7:51-59 (1993); Jurkiewicz and Sanguinetti, "Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent: Specific block of rapidly activating delayed rectifier K⁺ current by dofetilide", Circ. Res. 72:75-83 (1993)).

[0011] In view of the foregoing, it is clear the there is a need for new therapeutics for the treatment of cardiac disorders.

SUMMARY OF THE INVENTION

[0012] The embodiments disclosed herein relate to methods and compositions for the treatment and/or prevention of cardiac disorders.

[0013] Some embodiments disclosed herein provide a method of treating or preventing a cardiac disorder in a subject in need thereof. In some embodiments, the methods can include the steps of identifying a subject having or at risk of developing a cardiac disorder, and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a K201 metabolite, or pharmaceutically acceptable salt, ester, or amide thereof. Accordingly, in some embodiments, the method includes the step of administering a compound having the formula (I): formula (I)

[0014] to the subject.

[0015] Some embodiments provide for the treatment and/or prevention of atrial cardiac rhythm disorders, such as atrial bradycardia, atrial tachycardia, atrial fibrillation, or atrial flutter; ventricular cardiac rhythm disorders such as ventricular tachycardia (e.g., Torsades des Pointes, catecholaminergic polymorphic ventricular tachycardia, and monomorphic ventricular tachycardia, or the like) or ventricular fibrillation, or sudden cardiac death. Some embodiments provide methods of treating or preventing more than one cardiac disorder in a subject. For example, some embodiments provide methods of treating or preventing a cardiac arrhythmia, e.g., atrial fibrillation, in a subject that has heart failure, e.g., congestive heart failure or acute heart failure.

[0016] In some embodiments, the subject can be administered a K201 metabolite, or pharmaceutically acceptable salt, ester, or amide thereof, in an amount of about 500 to 1000 mg.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 is a graph of the concentration-response of the K201 metabolite M-II on the hERG potassium channel, as tested as described in Example 2.

[0018] Figure 2 is a graph of the concentration-response of the K201 metabolite M-II on the hNavl.5 sodium channel, as tested as described in Example 2.

[0019] Figure 3 is a graph of the concentration-response of the K201 metabolite M-II on the hKvl.5 potassium channel, as tested as described in Example 2.

[0020] Figure 4 is a graph of the concentration-response of the K201 metabolite M-II on the L-type calcium channels (hCavl .2), as tested as described in Example 2. [0021] Figure 5 is a graph of the concentration-response of the K201 metabolite M-II on the T-type calcium channels (hCav3.2), as tested as described in Example 2.

[0022J Figure 6 is a graph of the concentration-response of the K201 metabolite M-II on the hKir3.1/3.4 potassium channel, as tested as described in Example 2.

[0023] Figure 7 is a graph of the concentration-response of the K201 metabolite M-II on the hKir6.2/SUR2A potassium channels, as tested as described in Example 2.

[0024] Figures 8A-8B are graphs showing the effect of the K201 metabolite M-Il on the right atrial effective refractory period following administration, expressed in the ms (Figure 8A), or as a % increase from baseline (BL) (Figure 8B).

[0025] Figures 8C-8D are graphs showing the effect of the K201 metabolite M-II on the left atrial effective refractory period following administration, expressed in the ms (Figure 8C), or as a % increase from baseline (BL) (Figure 8D).

[0026] Figure 9 is a graph showing the effect of the K201 metabolite M-II on the left ventricular effective refractory period following administration, expressed in the ms.

[0027] Figures 10A-10B are graphs showing the effect of administration of the K201 metabolite M-II on inter-atrial conduction time, from the left atrium to right atrium (Figure 10A) and from the right atrium to the left atrium (Figure 10B).

[0028] Figures 1 IA-I IB are graphs showing the effect of administration of the K201 metabolite M-II on systolic, diastolic, and mean blood pressure, either before the measurement (Figure 1 IA), or after the measurements of atrial and ventricular effective refractory periods and conduction times (Figure 1 IB).

[0029] Figures 12A-12B are graphs showing the length of sinus cycle (in ms) over time, following infusion of the K201 metabolite M-II, either before the measurement (Figure 12A), or after the measurements of atrial and ventricular effective refractory periods and conduction times (Figure 12B)

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0030] K201 (4-[3-(4-benzylpiperidin-l-yl)propionyl]-7methoxy-2, 3, 4, 5- tetrahydro-l,4-benzothiazepine monohydrochloride) has been shown both in vitro and in vivo to have antiarrhythmic properties and is thus a candidate for development for treatment of arrhythmias in both the short term (termination of arrhythmia) and chronic settings (prevention of arrhythmia, or maintenance of sinus rhythm). K201 has also been shown to have a cardio protective effect, to be an effective suppressant of sudden cardiac cell death, and to prevent the onset of myocardial infarction. As discussed herein, Applicants have discovered that metabolites of K201 also have surprising and beneficial pharmacological properties that lend to their usefulness in the treatment and prevention of cardiac disorders.

[0031] The structure of K201, or JTV519, and its metabolites are shown in Table 1, below:

TABLE 1

[0032] As described below, Applicants discovered that metabolites of K201, including the M-II metabolite, have a blocking effect on cardiac ion channels. Accordingly, the compounds disclosed herein are useful in the treatment and prevention of cardiac diseases and disorders.

[0033] As used herein, the term "cardiac disorder," includes, but is not limited to disorders such as cardiac rhythm disorders, such as atrial cardiac rhythm disorders or ventricular cardiac rhythm disorders. Exemplary atrial cardiac rhythm disorders include atrial bradycardia, atrial tachycardia, atrial fibrillation, atrial flutter, other supraventricular rhythm tachycardias, and the like. Exemplary ventricular cardiac rhythm disorders include, but are not limited to ventricular tachycardia, e.g., Torsade des Pointes, catecholaminergic polymorphic ventricular tachycardia, and monomorphic ventricular tachycardia. The term "cardiac disorder" also encompasses conditions such as sudden cardiac death.

[0034] Among the embodiments disclosed herein are methods of preventing or treating cardiac disorders. Each of these methods comprises the step of administering to a subject in need thereof an effective amount of a K201 metabolite, or a pharmaceutically acceptable salt or derivative thereof. The preferred embodiments described herein also include compositions for preventing or treating cardiac disorders, comprising a K201 metabolite or a pharmaceutically acceptable salt, ester, amide thereof, and a pharmaceutically acceptable carrier, as well as uses of the compositions disclosed herein in the manufacture of medicament for the treatment and /or prevention of cardiac disorders. .

[0035] The term "pharmaceutically acceptable salt" refers to a formulation of a compound that does not cause significant irritation to a subject to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reacting a compound of the invention with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Pharmaceutical salts can also be obtained by reacting a compound disclosed herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like. Other exemplary salts include salts derived from organic acids, such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, benzoic, salicylic, sulfanilic, 2- acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic and the like; and salts derived from ammo acids, such as glutamic acid or aspartic acid.

[0036] The term "ester" refers to a chemical moiety with formula -(R)_n-COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1.

[0037] An "amide" is a chemical moiety with formula -(R)_n-C(O)NHR' or -(R)_n-NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), and where n is 0 or 1. An amide may be an amino acid or a peptide molecule attached to a compound of the embodiments disclosed herein, e.g., a K201 metabolite such as, for example M-II..

[0038] Any amine, hydroxy, or carboxyl side chain on the compounds disclosed herein, or esters, or amides of the compounds disclosed herein can be esterified or amidified. The procedures and specific groups to be used to achieve this end is known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.

[0039] The methods disclosed herein involve the administration of a therapeutically effective amount of a K201 metabolite, e.g., M-II, or an amide or ester thereof, to a subject in need thereof. The terms "subject," "patient" or "individual" as used herein refer to a vertebrate, preferably a mammal, more preferably a human. "Mammal" can refer to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sport, or pet animals, such as, for example, horses, sheep, cows, pigs, dogs, cats, etc. Preferably, the mammal is human.

[0040] In some embodiments described herein, the subject can be identified a "candidate" for a cardiac disorder. A "candidate" for a cardiac disorder is a subject who is known to be, or who is believed to be, or is suspected of being at risk for developing a cardiac disorder, or who is known to have, believed to have, or is suspected of having an existing cardiac disorder.

[0041] Those skilled in the art will appreciate that any routine diagnostic technique, or any combination of techniques, can be used to identify a subject that is a candidate for a cardiac disorder. By way of example, in some embodiments, the rate and regularity of a subject's heart are assessed by checking the subject's pulse, measuring the subject's systolic blood pressure and/or the subject's diastolic blood pressure.

[0042] In some embodiments, electrocardiograms and specialized ECGs can be used to assess the overall rhythm of the heart and weaknesses in different parts of the heart muscle in order to assess the presence of, or risk of development of, a cardiac disorder. For example, in some embodiments, an ECG is used to measure and diagnose abnormal cardiac rhythm disorders, including but not limited to abnormal cardiac rhythms caused by damage to the conductive tissue that carries electrical signals, or abnormal rhythms caused by abnormal electrolyte levels. In some embodiments, ECGs can be used to diagnose and identify damaged heart muscle caused by myocardial infarction (MI), for example.

[0043] In some embodiments, Stress Tests can be used to identify candidates that have, or at risk of developing either a cardiac rhythm disorder, or ischemia.

[0044] Electrophysiology (EP) Testing records the electrical activity and the electrical pathways of the heart. It is used to determine the cause of heart rhythm disturbances. Accordingly, in some embodiments, EP testing can be used to identify candidate subjects in the methods disclosed herein.

[0045] In some embodiments, a candidate subject is identified as having or as being at risk of developing, more than one cardiac disorder. For example, in some embodiments, the methods disclosed herein involve the identification of a subject that has heart failure, and that has, or is at risk of developing, atrial fibrillation. As such, the methods disclosed herein encompass the prevention of atrial fibrillation, e.g., in a subject that has heart failure. Likewise, the methods disclosed encompass the prevention or treatment of Torsade des Pointes in a subject with atrial fibrillation, or the like.

[0046] Embodiments of the methods disclosed herein involve the administration of a therapeutically effective amount of a K201 metabolite. A "therapeutically effective amount" as used herein includes within its meaning a non-toxic but sufficient amount of a compound or composition for use in the invention to provide the desired therapeutic effect. The exact amount of the K201 metabolite disclosed herein required will vary from subject to subject depending on factors such as the species being treated, the age and general condition of the subject, comorbidities, the severity of the condition being treated, the particular agent being administered and the mode of administration and so forth. Thus, it is not possible to specify an exact "effective amount". However, for any given case, an appropriate "effective amount" may be determined by one of ordinary skill in the art using only routine methods.

[0047] For example, in some embodiments, a therapeutically effective amount of the compounds disclosed herein is an amount sufficient to treat an existing cardiac disorder. By way of example, a "therapeutically effective amount" of the compounds disclosed herein can be an amount sufficient to arrest, stop, or reverse an existing cardiac arrhythmia, such as an atrial cardiac arrhythmia, e.g., atrial bradycardia, atrial tachycardia, atrial fibrillation, atrial flutter, or the like, as determined using conventional diagnostic methods. In some embodiments, a "therapeutically effective amount" of the compounds disclosed herein can be an amount sufficient to stop or reverse a ventricular cardiac arrhythmia, such as ventricular tachycardia, e.g., Torsade des Pointes, catcholaminergic polymorphic ventricular tachycardia, or monomorphic ventricular tachycardia, as determined using conventional diagnostic methods. In some embodiments, a therapeutically effective amount of the compounds disclosed herein is an amount effective to prevent a cardiac rhythm disorder, such as an atrial arrhythmia or a ventricular arrhythmia, as determined using conventional diagnostic methods. In some embodiments, a "therapeutically effective amount" of a compound disclosed herein is an amount sufficient to stop, arrest, or prevent sudden cardiac death. [0048] By way of example, a "therapeutically effective amount" can be, for example, 0.01 μg/kg, 0.1 μg/kg, 0.5 μg/kg, 1 μg/kg, 1.5 μg/kg, 2.0 μg/kg, 2.5 μg/kg, 3.0 μg/kg, 3.5 μg/kg, 4.0 μg/kg, 4.5 μg/kg, 5.0 μg/kg, 10 μg/kg, 15 μg/kg, 20 μg/kg.25 μg/kg, 30 μg/kg, 35 μg/kg, 40 μg/kg, 45 μg/kg, 50 μg/kg, 55 μg/kg, 60 μg/kg, 65 μg/kg, 70 μg/kg, 75 μg/kg, 80 μg/kg, 85 μg/kg, 90 μg/kg, 95 μg/kg, 100 μg/kg, 150 μg/kg, 200 μg/kg, 250 μg/kg, 300 μg/kg, 350 μg/kg, 400 μg/kg, 450 μg/kg, 500 μg/kg, 550 μg/kg, 600 μg/kg, 650 μg/kg, 700 μg/kg, 750 μg/kg, 80 μg/kg 0, 850 μg/kg, 900 μg/kg, 1 mg/kg, 1.5mg.kg, 2.0 mg/kg, 2.5 mg/kg, 3 mg/kg, 4.0mg/kg, 5.0 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg 50 mg/kg, 55 mg/kg, 60 mg/kg, 65 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 85 mg/kg, 90 mg/kg, 95 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 350 mg/kg, 400 mg/kg, 450 mg/kg, 500 mg/kg, 550 mg/kg, 600 mg/kg, 650 mg/kg, 700 mg/kg, 750 mg/kg, 800 mg/kg, 850 mg/kg, 900 mg/kg, 950 mg/kg, lg/kg, 5 g/kg, 10 g/kg, or more, or any fraction in between. Accordingly, in some embodiments, the dose of K201 metabolite administered to the subject can be 0.1 mg, 1 mg, 2mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg,, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 220 mg, 240 mg, 260 mg, 280 mg, 300 mg, 320 mg, 340 mg, 360 mg, 380 mg, 400 mg, 420 mg, 440 mg, 460 mg, 480 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1 g, or more, or any amount in between. The exemplary therapeutically effective amounts listed above, can, in some embodiments be administered on an hourly basis, e.g., every one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three hours, or any interval in between, or on a daily basis, every two days, every three days, every four days, every five days, every six days, every week, every eight days, every nine days, every ten days, every two weeks, every month, or more or less frequently, as needed to achieve the desired therapeutic effect.

[0049] The skilled artisan will appreciate that dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

[0050] Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[0051] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0052] In some embodiments, the K.201 metabolite, e.g., M-II can be administered parenterally, such as intramuscular Hy, subcutaneously, intravenously, via intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections or the like. Preferably, the K201 metabolite, e.g., M-II, can be provided intravenously in a continuous infusion.

[0053] In some embodiments, the K201 metabolite, e.g., M-II is provided in a single dose during the administration. For example, in some embodiments, about 2 mg/kg, 3 mg/kg, 4 mg/kg or more of the K201 metabolite, e.g., M-II, can be provided in a single dose, for example in a continuous intravenous infusion. In some embodiments, the K201 metabolite, e.g., M-II is provided in more than one dose during the administration, for example, two, three or more doses of the K.201 metabolite, e.g., M-II can be provided in a single continuous intravenous infusion.

[0054] In some embodiments, the K201 metabolite, e.g., M-II, can be provided in a continuous infusion for a period of time of about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, about 12 hours, about 13 hours, about 14 hours, about 15 hours, about 16 hours, about 17 hours, about 18 hours, about 19 hours, about 20 hours, about 21 hours, about 22 hours, about 23 hours, about 24 hours, or more. Preferably, the K201 metabolite, e.g., M-II, can be provided in a continuous infusion for a period of time of about 3 hours, 3.5 hours, 4 hours, 4.5 hours, or 5 hours, 5.5 hours, 6 hours, or 6.5 hours, or any amount of time in between. In some embodiments, two doses of the K201 metabolite, e.g., M-II ,can be provided in a continuous infusion over a period of about 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, or 7 hours. Optionally, the first dose can be provided over about 1.5 to about 2.5 hours, preferably 2 hours, and the second dose can be provided over about 3.5 hours, 4 hours, or 4.5 hours, preferably about 4 hours.

[0055] In some embodiments, the K201 metabolite, e.g., M-II, or a pharmaceutically acceptable salt, ester, or amide thereof is administered orally. A description of carrier materials useful in the oral formulations described herein can be found in the Remington: The Science and Practice of Pharmacy (20^th ed, Lippincott Williams & Wilkens Publishers (2003)), which is incorporated herein by reference in its entirety.

[0056] Some embodiments provided herein relate to pharmaceutical compositions comprising a KW-3902 metabolite as described above, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.

[0057] In some embodiments, the methods involve the administration of a pharmaceutical composition that comprises one of the compounds disclosed herein, e.g., a K201 metabolite such as M-II, or a pharmaceutically acceptable salt, ester, or amide thereof. The term "pharmaceutical composition" refers to a mixture of a compound of the invention with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0058] The term "carrier" defines a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

[0059] The term "diluent" defines chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

[0060] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0061] The pharmaceutical compositions described herein can be administered to a human subject per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0062] Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.

[0063] Alternatively, one can administer the compounds disclosed herein in a local rather than systemic manner, for example, via injection of the compound directly in the cardiac area, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.

[0064] In some embodiments, the subjects identified herein are administered a second therapeutic agent, in combination with the K201 metabolite(s) disclosed herein. For example, in some embodiments provided herein, the subject to be treated by the methods described herein can be administered a K201 metabolite, e.g., M-II or a pharmaceutically acceptable salt, ester, or amide thereof in combination with an inotropic drug, such as amrinone, inamrinone, milrinone, calcium, levosimendan, digoxin, dobutamine, dopamine, dopexamine, epinephrine, isoprenaline, norepineprine, prostaglandins, enoximone, and theophyilline; a phosphodiesterase-III inhibitor, a beta blocker, such as alprenolol, cateolol, levobunolol, mepindolol, metipranolol, nadolo, oxpernolol, penbutolol, pindolol, proanolol, sotalol, tiolol, acebutolol, atenolol, betaxolol, bisoprolol, esmolol, metoprolol, nebivolol, amosulalol, landiolol, tilisolol, arotinolol, carvedilol, celiprolol, labetalol, butexamine; a calcium channel blocker, such as nifedipine, verapamil, diltiazem, amlodipine, clevidpipine, felodipine, isradipine, nicardipine, nimodipine, nisolipine, verapamil, or the like; an angiotensin II receptor blocker, such as loartan, valsartan, irbesatran, candesartan, or the like; an aldosterone inhibitor, such as spironolactone, andeplerenone, triamterene, an antiarrhythmic agent, such as quinidine, procainamide, disopyramide, lidocaine, mexiletine, toca inide phenytoin, ecainide, f lecainide, moricizine, propafenone, azimilide, bretylium, clofilium, dofetilide, tedisamil, ibutilide, sematilide and sotolol, and adenosine, or any other therapeutic known or used in the treatment or prevention of cardiac disorders. In some embodiments, the subjects identified herein can be administered a K201 and a combination of additional therapeutic agents, such as those listed herein.

[0065] In some embodiments, the administering step comprises administering said other therapeutic and said K201 metabolite, e.g., M-II or a pharmaceutically acceptable salt, ester, or amide thereof nearly simultaneously. These embodiments include those in which the K201 metabolite e.g., M-II or a pharmaceutically acceptable salt, ester, or amide thereof and the other therapeutic are in the same administrable composition, i.e., a single tablet, pill, or capsule, or a single solution for intravenous injection, or a single drinkable solution, or a single dragee formulation or patch, contains both compounds. The embodiments also include those in which each compound is in a separate administrable composition, but the subject is directed to take the separate compositions nearly simultaneously, i.e., one pill is taken right after the other or that one injection of one compound is made right after the injection of another compound, etc.

[0066] In some embodiments, the methods described herein can include the step of measuring the presence or existence of symptoms or signs associated with the cardiac disorder, following administration of the K201 metabolite, or pharmaceutical composition comprising the K201 metabolite to the subject. In some embodiments, the administration of the K201 metabolite, e.g., M-II or a pharmaceutically acceptable salt, ester or amide thereof transforms the mammal, such that the cardiac condition is lessened, treated or prevented in the mammal. For example, in some embodiments, the administration of the K201 metabolite, or pharmaceutical composition comprising the K201 metabolite causes a cessation or an amelioration of a cardiac rhythm disorder in a subject with an existing cardiac rhythm disorder, or, preserves normal sinus rhythm in a subject at risk of developing a cardiac rhythm disorder.

[0067] Embodiments disclosed herein also relate to pharmaceutical compositiosn that consist of, consist essentially of, or comprise, a K201 metabolite, e.g., M-II or a pharmaceutically acceptable salt, ester, or amide thereof. Pharmaceutical compositions disclosed herein can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

[0068] Pharmaceutical compositions for use in accordance with the embodiments described herein thus can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well- known techniques, carriers, and excipients can be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.

[0069] For injection, the agents of the invention may be formulated in aqueous solutions or lipid emulsions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.

[0070] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidore, agar, or alginic acid or a salt thereof such as sodium alginate. [0071] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0072] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Furthermore, the formulations of the present invention may be coated with enteric polymers. All formulations for oral administration should be in dosages suitable for such administration.

[0073] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0074] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0075] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

[0076] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0077] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0078] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0079] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0080] A pharmaceutical carrier for the compounds described herein can be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant POLYSORBATE 80 , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80^™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

[0081] Alternatively, other delivery systems for the pharmaceutical compounds disclosed herein may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0082] Many of the compounds used in the pharmaceutical combinations described herein can be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.

[0083] Pharmaceutical compositions suitable for use in the embodiments described herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of the cardiac disorder, or prolong the survival, of subject being treated. As discussed herein, determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0084] The compositions may, if desired be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0085] Having now generally described the invention, the same will become better understood by reference to certain specific examples which are included herein for purposes of illustration only and are not intended to be limiting unless other wise specified. All referenced publications and patents are incorporated, in their entirety by reference herein.

EXAMPLE 1 [0086] An exemplary pathway for the synthesis of M-II is depicted in Scheme 1, below: Scheme

M-II X-H [0087] Referring to scheme 1, in step (a), 5-methoxy-2nitrobenzoic acid (SIGMA Aldrich, Cat. No. 391999, St. Louis, MO), is treated with a reducing agent, in the presence of an optional catalyst, for example, H₂, Pd/C, MeOH, at room temperature, as described in U.S. Patent Application Publication No. 2004/0229871. In step (b), the compound formed in step (a) is treated with a diazotizing agent and a disulfide, for example, NaNO₂, HC1/H₂, Na₂S₂, e.g., as described in J. Med. Chem. ( 1982) 25:220. The compound formed in step (b) can be treated with a chloride and a chloroethylamine, such as SOCl₂ followed by H₂NCH₃CH₂Cl, H₂NCH₂Cl, or the like. The compound formed in step (c) can be reduced/cyclized by treating the compound with sodium borohydride or the like, in ethanol, as described in J. Heterocyl. Chem (1988), 25: 1007 or Eur. J. Med. Chem. Chim. Ther. (1993) 28(3):213. The compound formed in step (d) can be treated with BH₃, LiAlH₄, or the like, to form an amine. The compound formed in step (e) can be treated with acryloyl chloride or the like in a solvent such as toluene in the presence of Na2Co3, or the like. The compound formed in step (f) can be oxidized with we/α-chloroperbenzoic acid in dichloromethane at a low temperature. Finally, the compound formed in step (g) can be converted to the target molecules, e.g., M-II or labeled M-II by treating with 4-benzylpiperidine or labeled 4-benzylpiperidine as described, e.g., in J Am. Chem. Soc. (1957) 79:3805.

[0088] The following example describes experiments to determine the effects of K201 metabolites on various cardiac ion channels.

EXAMPLE 2

[0089] In a study conducted to measure the in vitro effect of K201 metabolites, mammalian cells were stably transfected with the cloned human genes encoding the cardiac ion channels listed in Table 2.

[0090] Stock solutions of K201, K201 M-II and control solutions were prepared in dimethyl sulfoxide (DMSO) and stored frozen. Fresh dilutions of the stock were made in HEPES buffered saline, such that final test formulations did not exceed a DMSO concentration of >0.3%. For each ion channel tested, a positive control was prepared. The identity of the positive controls is listed in Table 2.

[0091] Table 2 lists the cardiac ion channels tested: TABLE 2

[0092] A glass-lined 96 well compound plate was loaded with the appropriate amounts of test and control solutions and placed in the well of a PATCHXPRESS® ion channel reader (Model 7000A, Molecular Devices, Union City, CA). Cell Culture Procedures: [0093] HEK293 cells were stably transfected with the appropriate ion channel cDNA encoding the pore-forming channel subunit. Stable transfectants were selected using the G418- resistance gene incorporated into the expression plasmid. Selection pressure was maintained with G418 in the culture medium. Cells were cultured in D-MEM/F-12 (Dulbecco's Modified Eagle Medium/Nutrient Mixture F- 12) supplemented with 10% FBS, 100 U/mL penicillin G sodium, 100 μg/mL streptomycin sulfate and 500 μg/mL G418.

[0094] CHO cells were stably transfected with the appropriate ion channel cDNAs. Cells were cultured in Ham's F-12 supplemented with 10% FBS, 100 U/mL penicillin G sodium, 100 μg/mL streptomycin sulfate, and the appropriate selection antibiotics. Before testing, cells in culture dishes were washed twice with Hank's Balanced Salt Solution, treated with trypsin, and re-suspended in the culture media (4-6 x 10⁶ cells in 20 mL). Cells in suspension were allowed to recover for 10 minutes in a tissue culture incubator set at 37⁰C in a humidified 95% air/5% CO₂ atmosphere. Test Methods

[0095] All experiments were performed at room temperature.

[0096] Four concentrations, i.e., OA, 1, 10 and 100 μM, of K201 Mil were applied at 5 minute intervals to naϊve cells (n > 2), where n= the number cells/concentrations; up to 2 concentrations/cell). Solution exchanges were performed in quadruplicate, and consisted of aspiration and replacement of 45 μL of the total 50 μL volume of the extracellular well of the SEALCHIP™ planar voltage clamp tool. Duration of exposure to each test article concentration was 5 min.

TABLE 3

[0097] For the positive control treatment groups, vehicle was applied to naϊve cells (n > 2, where n= the number cells), for a 5-10 minute exposure interval. Each solution exchange, performed in quadruplicate, consisted of aspiration and replacement of 45 μL of the total 50 μL volume of the extracellular well of the SEALCHIP™ planar voltage clamp tool. After vehicle application, the positive control was applied in the same manner, to verify sensitivity to ion channel blockade.

[0098] Intracellular solution (Table 4) was loaded into the intracellular compartments of the SEALCHIP™ planar voltage clamp tool. Cell suspension was pipetted into the extracellular compartments of the SEALCHIP™ planar voltage clamp tool. After establishment of a whole-cell configuration, membrane currents were recorded using dual-channel patch clamp amplifiers in the PATCHXPRESS® ion channel reader. Before digitization, the records were low-pass filtered at one-fifth of the sampling frequency. Valid whole-cell recordings met the following criteria: 1) Membrane Resistance (Rm) > 200 MΩ; and 2) Leak current < 25% channel current. hERG Test Procedure

[0099] Onset and block of hERG current was measured using a stimulus voltage pattern consisting of a 500 ms prepulse to -4OmV (leakage subtraction), a 2-second activating pulse to +40 mV, followed by a 2-second test pulse to -40 mV. The pulse patter was repeated continuously at 10 second intervals, from a holding potential of -80 mV. Peak tail current was measured during the -40 mV test pulse. Leakage current was calculated from the current amplified evoked by the prepulse and subtracted from the total membrane current record. hNayl .5 Test Procedure

[0100] Onset and steady-state block of hNavl.5 current was measured using a double pulse pattern consisting of a hyperpolarizing conditioning pulse (-10OmV amplitude, 200 ms duration) followed immediately by a depolarizing test pulse depolarization (-15 mV amplitude, 10 ms duration), form a holding potential of -80 mV. The pulse pattern was repeated at 10 second intervals. Peak and test pulse current amplitudes were measured. hCayl.2 Test Procedure

[0101] Onset and steady state block of hCavl .3/β2 channels was measured using a stimulus voltage pattern consisting of a depolarizing test pulse (duration, 200 ms; amplitude, 10 mV) at 10 second intervals from a -80 mV holding potential. Test article concentrations were applied cumulatively in ascending order without washout between applications. Peak current was measured during the step to 10 mV. 10 μM of nifedipine was added at the end of each experiment to block hCavl .2 current. Leak current was digitally subtracted from the total membrane current record. hKvLQTl/hminK Test Procedure

[0102] Onset and steady state block of hKvLQTl/hminK current was measured using a pulse pattern with fixed amplitudes (depolarization; +40 mV for 2 seconds; repolarization: -40 mV for 0.5 seconds) repeated at 15 second intervals from a holding potential of -80 mV. Current amplitude was measured at the end of the step to +40 mV. 300 μM of Chromanol 293B was added at the end of each experiment to block hKvLQTl/hminK current. Leakage current was measured after chromanol 293B addition, and subtracted from the total membrane current record. hKv4.3 Test Procedure

[0103] Onset and steady state block of hKv4.3 current were measured using a pulse pattern with fixed amplitudes (depolarization: 0 mV for 300 ms,), repeated at 10 second intervals from a holding potential of -80 mV. Peak and sustained test pulse current amplitudes were measured during the step to zero mV. hKyl.5 Test Procedure

[0104] Onset and steady state block of hKvl.5 current was measuring using a pulse pattern with fixed amplitudes (depolarization: +20 mV amplitude, for 300 ms) repeated at 10 second intervals from a holding potential of -80 mV.. Current amplitude was measured at the end of the step to +20 mV. hCav3.2 Test Procedure

[0105] Onset and steady state block of hCav3.2 current was measured using a double pulse pattern consisting of a hyperpolarizing conditioning pulse (-120 mV amplitude, 250 ms duration) followed immediately by a depolarizing test pulse depolarization (-30 mV amplitude, 50 ms duration) from a -80 mV holding potential. The pulse pattern was repeated at 10 second intervals and peak test current amplitudes were measured. hKir2.1 Test Procedure

[0106] Onset and steady state block of hKir2.1 current was measuring using a pulse pattern with fixed amplitudes (hyperpolarization: -1 10 mV amplitude, for 300 ms) repeated at 10 second intervals from a holding potential of -70 mV.. Current amplitude was measured at the end of the step to -1 10 mV. hKir3. l/hKir3.4 Test Procedure

[0107] Onset and steady state block of hKir3. l/hKir3.4 current was measuring using a pulse pattern with fixed amplitudes (hyperpolarization: -100 mV amplitude, for 400 ms), followed by a 1 -second ramp from -100 mV to +40 mV) repeated at 10 second intervals from a holding potential of -70 mV.. Current amplitude was measured at the end of the step to -100 mV. hHCN2 Test Procedure

[0108] Onset and steady state block of hHCN2 current was measuring using a pulse pattern with fixed amplitudes (hyperpolarization: -120 mV amplitude, for 1 second) repeated at 10 second intervals from a holding potential of -30 mV. Current amplitude was measured at the end of the step to -120 mV. hHCN4 Test Procedure

[0109] Onset and steady state block of hHCN4current was measuring using a pulse pattern with fixed amplitudes (hyperpolarization: -120 mV amplitude, for 1 second) repeated at 10 second intervals from a holding potential of -30 mV. Current amplitude was measured at the end of the step to -120 mV.

[0110] hKir6.2/SUR2A Test Procedure

[0111] The hKir6.2/hSUR2A current was activated with a 5 minute application of 100 μM pinacidil. Onset and steady state block of the current was measured using a pulse patter with fixed amplitudes (hyperpolarization: -1 10 mV amplitude, for 400 ms), followed by a 1- second ramp from -100 mV to +10 mV) repeated at 10 second intervals from a holding potential of -60 mV.. Current amplitude was measured at the end of the step to +10 mV.

TABLE 4

I

NJ OO I

Data Analysis

[0112] Data was analyzed using conventional software. Steady sate is defined by the limiting constant rate of change with time (linear time dependence). The steady state before and after teat article application was used to calculate the percentage of current inhibited at each concentration. Concentration-response date was fit to an equation of the following form:

% Bock = { l-l/[l+([Test]/IC₅₀)^N]} * 100

[0113] where [Test] is the concentration of M-II, IC₅₀ is the concentration of M-II producing half-maximal inhibition, N is the Hill coefficient, and % Block is the percentage of ion channel current inhibited at each concentration of the test article. Nonlinear test squares fits will be solved with the Solver add-in for Excel 2000 Microsoft, Redmond, WA). If the test article produced greater than 50% block at the highest concentration, IC₅₀ was established.

[0114] The effect of K201 M-II on cardiac ion channels (expressed in the mammalian cell lines indicated above) was evaluated at room temperature using the PatchXpress™ 7000A parallel patch clamp system (Molecular Devices, Sunnyvale, CA). The K201 metabolite M-II was evaluated at 0.1, 1, 10 and 100 μM, with each concentration tested on 2-3 cells (n > 2). The duration of exposure to each test article concentration was 5 minutes.

[0115] Under the experimental conditions the K201 metabolite M-II blocked Iκ_r (hERG) channels in a concentration dependent fashion yielding an IC₅₀ value of 1.328 μM. (Table 2, Figure 1).

[0116] Under the experimental conditions the K201 metabolite M-II blocked Iκ_r (hERG) channels in a concentration dependent fashion yielding an IC₅₀ value of 0.372 μM. (Table 5, Figure 1).

TABLE 5

[0117] Under the experimental conditions the K201 metabolite M-II free base blocked I_NS (hNal .5) sodium channels in a concentration dependent fashion yielding an IC₅₀ value of 8.333 μM. (Table 6, Figure 2).

TABLE 6

[0118] Under the experimental conditions the K201 metabolite M-II blocked Iκ_s (hKvLQTl/hminK) potassium channels in a concentration dependent fashion yielding an IC₅₀ value of > 100 μM. (Table 7).

TABLE 7

[0119] Under the experimental conditions the K201 metabolite M-II blocked I₁₀ (hKv4.3) potassium channels in a concentration dependent fashion yielding an IC₅₀ value of 50.225 μM. (Table 8).

TABLE 8

[0120] Under the experimental conditions the K201 metabolite M-II blocked Iκ_Ur (hKvl .5) potassium channels in a concentration dependent fashion yielding an IC₅₀ value of 4.994 μM. (Table 9, Figure 3).

TABLE 9

[0121] Under the experimental conditions the K201 metabolite M-II blocked Ic_a,L (hCavl .2) calcium channels in a concentration dependent fashion yielding an IC₅₀ value of 1.129 μM. (Table 10, Figure 4).

TABLE 10

[0122] Under the experimental conditions the K201 metabolite M-II blocked Ic_a,i (hCav3.2) calcium channels in a concentration dependent fashion yielding an IC₅₀ value of 49.172 μM. (Table 11, Figure 5).

TABLE 11

[0123] Under the experimental conditions the K201 metabolite M-II blocked Iκi(hKir2.1) potassium channels in a concentration dependent fashion yielding an IC₅₀ value of≥lOO μM. (Table 12).

TABLE 12

[0124] Under the experimental conditions the K201 metabolite M-II blocked I_f (hHCN2) potassium channels in a concentration dependent fashion yielding an IC₅₀ value of >100 μM. (Table 13).

TABLE 13

[0125] Under the experimental conditions the K201 metabolite M-II blocked I_f (hHCN4) potassium channels in a concentration dependent fashion yielding an IC₅₀ value of >100 μM. (Table 14).

TABLE 14

[0126] Under the experimental conditions the K201 metabolite M-II blocked Uch (hKir3.1/hKir3.4) potassium channels in a concentration dependent fashion yielding an IC50 value of 40.524 μM. (Table 15, Figure 6).

TABLE 15

72.5

100 74.6 3.0 2.1

76.7

[0127] Under the experimental conditions the K201 metabolite M-II blocked Ii_CATP (hKir6.2/SUR2A) potassium channels in a concentration dependent fashion yielding an IC₅₀ value of 6.820 μM. (Table 16, Figure 7).

TABLE 16

[0128] The data above demonstrate that K201 metabolites possess properties that render them useful in the treatment and/or prevention of cardiac disorders, such as cardiac rhythm disorders, e.g., atrial cardiac rhythm disorders or ventricular cardiac rhythm disorders, including atrial bradycardia, atrial tachycardia, atrial fibrillation, atrial flutter, ventricular tachycardia {e.g., Torsade des Pointes, catecholaminergic polymorphic ventricular tachycardia, and monomorphic ventricular tachycardia), as well as disorders such as sudden cardiac death, acute and/or chronic cardiomyopathy, (e.g., left ventricular systolic dysfinction or left ventricular diastolic dysfunction), acute coronary syndrome, such as myocardial infarction, angina, acute and/or chronic hypertension, (e.g., catecholamine-induced hypertension), pulmonary edema, chronic obstructive pulmonary disease and the like.

EXAMPLE 3 M-II Effects on Atrial Effective Refractory Period in vivo

[0129] The anesthetized dog model is a standard model for cardiovascular pharmacology investigations. Accordingly, anesthetized mongrel dogs were used, as described below, to determine the dose dependent increase in atrial effective refractory period (AERP) of K201 metabolite M-II and corresponding plasma levels of M-II, and to determine the effects of M-II on the surface ECG at designated dose levels.

[0130] The test article dosing formulations were administered intravenously to anesthetized mongrel dogs as shown in Table 19.

TABLE 19

[0131] ** Initial infusion of 0/3 mg/kg/min for 2 minutes, followed by 0.03 mg/kg/min for 30 minutes

[0132] ***Dose based on mg M-II free-base. Dosing formulation is 1.39 mg/mL M-II free base (2 mg/mL M-II citrate salt). Test System

[0133] Upon arrival, dogs were individually housed in pens equipped with an automatic watering system. A standard commercial dog chow (approximately 800 g, Hill's, Prescription Diet IiD) was made available to each dog once daily. Animals were fasted overnight prior to surgery.

[0134] Prior to each animal's treatment, the following surgical procedure was performed on each animal. All dogs were administered morphine (2 mg/kg subcutaneously) 19-22 minutes prior to induction of anesthesia. Dogs were anesthetized with a bolus of 2.5% a-chloralose at 120 mg/kg IV, followed by a constant infusion of a-chloralose at 33 mg/kg/hr IV, administered in the right or left femoral vein. One (1) animal (1003B) however, had its infusion reduced (57 minutes post initiation of the dosing) and stopped for 5 minutes (at 116 minutes post initiation of the dosing) due to low arterial blood pressure, and another animal (100 I A), had its infusion reduced to 25 mg/kg/hr (at 199 minutes post initiation of dosing) also due to low arterial blood pressure during the experiment.

[0135] Additional morphine injections of at a dose of 0.5 mg/kg per injection were administered subcutaneously approximately every 2 hrs to maintain the level of analgesia throughout the experiment. Dogs were placed on a heating pad set to maintain the animal's body temperature at approximately 37°C. Body temperature was monitored throughout the experiment via a rectal thermometer. Dogs were intubated and provided assisted ventilation supplemented with oxygen and medical air to maintain oxygenation within the normal physiologic range. The animals were mechanically ventilated using a rebreathing system at a rate 20 breaths/minute, a tidal volume of 13 mL/kg and an inspiratory pressure of 19-20 CmH₂O. Lidocaine 2% was not used during intubation as the animals did not present signs of reflexes. The following parameters were regularly monitored in order to ensure proper ventilation of the animals but will not be reported: SpO₂, inspiratory and expiratory CO₂, inspiratory O₂ and respiratory rate.

[0136] For each dog, a fluid filled catheter system with transducer was used to measure the arterial pressure from the femoral artery. A sternotomy was performed, and the pericardium opened from which a sling was created for the heart. With the heart exposed, epicardial bipolar pacing and recording electrodes were placed on the right and left cardiac atrial and ventricular appendages. In addition, an indwelling catheter was placed in the right femoral or saphenous vein for administration of Lactated Ringer's at 10 mL/kg/hr throughout the course of the anesthesia. In one (1) animal (1003B) out of three (3), this rate was increased to approximately 20 ml/kg/hr (500 ml/hr) for 13 minutes due to low arterial blood pressure.

[0137] Following surgical preparation and instrumentation, hemodynamic and electrocardiographic parameters were allowed to stabilize for at least 30 minutes. Preparation of Dosing Formulations

[0138] Each formulation was prepared by dissolving the appropriate amount of Sorbitol into 2/3 of the final volume of Sterile Water for Injection USP under continuous stirring for 5 minutes or until the solution was clear. The formulation's pH was adjusted under continuous stirring using a citric acid monohydrate (with an approximate ratio of 0.34 mg/mL of solution), to reach a pH in the range of 3.0 to 4.0. The appropriate amount of test article powder was then weighed (2 mg M-II citrate salt/mL) and added into the solution. The preparation was mixed until completely dissolved (using a magnetic stir plate) and the pH was recorded. Finally, the pH of the formulation was adjusted using a solution of O. IN NaOH, to reach a pH of 3.25±0.1. The preparation was then made up to the final volume with Sterile Water for Injection USP in order to reach the required concentration. The final pH was then recorded as 3.00 to 3.30.

[0139] The formulations were filtered through a 0.2211m Polyethersulphone (PES) filter into an amber glass vial, or a clear glass vial covered with aluminum foil. Administration of M-II

[0140J Each dose was administered intravenously as an infusion consisting of an initial infusion of 0.3 mg/kg/min for 2 minutes followed by 0.03 mg/kg/min for 30 minutes via the left saphenous vein.

[0141] All dosings were undertaken as set forth above, with the exception that due to unknown reason, the initial infusion (0.3 mg/kg/min for 2 minute) for one dog terminated 27 seconds earlier while presenting a positive deviation of 1 1.83% above theoretical dose volume. One dog also presented a positive deviation of 14.37% above theoretical dose volume for the same infusion but terminated the infusion as indicated. The remaining dosings occurred without any notable deviations from theoretical doses. Surface Electrocardiography

[0142] Prior to treatment, electrocardiograms (limb leads I, II and III and leads a VR, a VL and a VF) were obtained from all animals and evaluated in order to ensure suitability for use on the study.

[0143] During the treatment period, ECG waveforms were monitored and recorded continuously using the Dataquest ART 3.01 Telemetry system via a transmitter (TL1OM3-D70-EEE) connected using external leads. Average values for lead II were calculated over 5 seconds due to pacing. The QT interval was corrected for heart rate changes using the Fredericia's and Van de Water's formulas. Computer analysis of ECG intervals (RR, PR, QRS, QT and QTc) was performed at approximately the following timepoints in all treatment groups: before infusion, continuously during infusion (approximately at 1 minute interval), at 10-minute intervals for the first 30 minutes post infusion, and at 20-minute intervals for the remainder of the study (total = 4 hours after completion of infusion).

[0144] Tracings were assessed for gross changes indicative of cardiac electrical abnormalities. Heart rate (lead II), rhythm or conduction abnormalities, QT and corrected QT (QTc) intervals were also evaluated. Tabular data of heart rates and QT and QTc intervals are presented for animals 1 through 3 in Tables 20-22, respectively.

TABLE 20

Atrial Effective Refractory Period and Conduction Time Determinations

[0145] A programmable stimulator (Caltronics Inc.) connected to pacing cables was used for atrial pacing. Initially, the right and left atrial diastolic pacing threshold were determined at 2 msec pulse duration, by decrementing pulse amplitude (mA) gradually until consistent loss of atrial capture was observed. Subsequently, the pulse amplitude was increased to approximately twice this value. To determine atrial effective refractory period (AERP), pacing from right and left atrial epicardial bipolar electrodes was done sequentially at basic drive cycle lengths (S 1 S 1) of 360, 300, and 200 msec for eight (8) beats. Then, a premature atrial stimuli (S1S2) was introduced, decrementing by 5 msec after each drive cycle to determine AERP. AERP was defined as the longest S1S2 interval that did not produce atrial capture. Similar measurements were performed to determine the left-ventricular ERP at an SlSl of300 ms. Also, inter-atrial conduction time was used to provide an estimate of atrial conduction velocity since the distance between electrodes was constant but unknown. Inter- atrial conduction time was determined once during each drive cycle (SlSl 360, 300 and 200 msec) by measuring the stimulus to contralateral local atrial electrocardiogram interval. All measurements were performed at baseline prior to infusion, 15 minutes into the infusion (for Group 1), immediately after completion of infusion, at 30 minutes, 1 hour, 2 hours and 4 hours after completion of infusion. ECG intervals were measured using a computerized system (Grasslab®, Astro-Med Inc.).

[0146] AERP and VERP measurements are shown in Figures 8A-8D and Figure 9. As shown, the K201 metabolite M-II increased atrial ERP with a slight reverse use- dependency. The significant effects lasted more than 2 and 4 hours in the left atrium (Figures 8A-8B) and right atrium (Figures 8C-8D), respectively. The K201 metabolite M-II did not affect left ventricular ERP (Figure 9). Conduction time measurements are depicted graphically in Figures 10A-10B. The K201 metabolite M-II did not affect intra-atrial conduction time. Blood pressure measurements are depicted graphically in Figures HA- HB. The K201 metabolite M-II caused a mild downward drift in blood pressure, suggesting that K201 has hypotensive tendencies. Sinus cycle length changes are depicted graphically in Figures 12A-12B. Sinus cycle length decreased consistently during the experiment. The time course of the changes were slower compared to atrial ERP changes and were progressive, rather than concentration-dependent. Toxicokinetic Profiling

[0147] Venous blood samples (-1.3 mL/sample) were collected from the left jugular or left femoral at the following timepoints: [0148] o Pre-Rx

[0149] o Immediately post end Rx 1 (end of first infusion) [0150] o 15 min post start Rx 2 (i.e., during the second infusion) [0151] o immediately post end Rx 2 (i.e. at the end of infusion) [0152] o and at 30 minutes, 1 hour, 2 hours and 4 hours post end Rx 2 [0153] Blood samples were collected into tubes containing lithium heparin. Samples were centrifuged at 1500 g for a minimum of 10 minutes. The plasma was transferred into 2 aliquots containing at least 0.25 mL. Each plasma sample was placed on dry ice and then stored frozen (-70⁰C ± 10⁰C), pending shipment, on dry ice, to MicroConstants, San Diego, CA. Results

[0154] As expected for an IKr blocker, infusion of K201 metabolite M-II at 1500 μg/kgu(300 μg/kg/minute x 2 minute followed by 30 μg/kg/minute x 30 minute), presented evidence of QTc prolongation ranging from + 11 to +25 msec immediately post initiation of the administration (1 min post-dosing start). QTc prolongation attained +25 to +37 msec during dosing and was relatively sustained throughout the monitoring period. However, beginning at 16 minutes post initiation until completion of dosing, variable changes in QTcV were observed which returned to elevated levels (+16 to +25 msec) by the end of the dosing period. Concurrently, heart rate presented variations that correlated with the QTcV changes.

[0155] Once the dosing was completed, a second series of changes occurred (beginning at 32 to 62 minutes post initiation of dosing) where a slight to severe decrease in QTcV was observed. In two animals out of three, this decrease brought the original QT prolongation to baseline levels, while for one animal out of three this decrease resulted in a QT shortening (-45 msec). These observations were correlated with moderate to severe increase in heart rate reaching +42% to + 109% from baseline values. [0156] Significant PR interval changes were only observed in one animal out of three, and between 2 and 1 1 min post initiation of the test article administration. This period presented evidence of PR prolongation (+9 to + 16 msec) reaching + 12.5%, while heart rate presented variation which ranged between -0.6% to +4.7%. Part of this prolongation may be due to the decreased heart rate but a drug effect (e.g. calcium channel block) may also be involved. Atrial Effective Refractory Period and Conduction Time Determinations

[0157] M-II produced clear atrial ERP increases that were important in both atria. The increases were substantial and had the time course expected for a direct drug action. These changes would be expected to translate into antiarrhythmic actions against reentrant atrial arrhythmias, especially AF. The drug had no discernible effects on ventricular ERP or inter-atrial conduction time.

[0158] Drug infusion was associated with small changes in blood pressure (slight decrease) and sinus rate (slight to moderate fastening). These actions would not be expected to impair antiarrhythmic properties or cause untoward side effects even if they are drug- related.

[0159] The electrophysiological results described herein demonstrate that M-II has atrial antiarrhythmic properties in vivo, confirming its usefulness as a therapeutic for treating and preventing cardiac rhythm disorders.

Claims

WHAT IS CLAIMED IS:

1. A method of treating or preventing a cardiac rhythm disorder in a subject in need thereof, comprising: identifying a subject having or at risk of developing a cardiac rhythm disorder; and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound having the formula (I): formula (I)

or a pharmaceutically acceptable salt, ester or amide thereof.

2. The method of Claim 1, wherein the cardiac rhythm disorder is an atrial rhythm disorder.

3. The method of Claim 2, wherein the atrial rhythm disorder is atrial fibrillation.

4. The method of Claim 2, wherein the atrial rhythm disorder is atrial flutter.

5. The method of Claim 2, wherein the atrial rhythm disorder is a supraventricular tachycardia.

6. The method of Claim 1 , wherein the cardiac rhythm disorder is a ventricular rhythm disorder.

7. The method of Claim 6, wherein the ventricular rhythm disorder is catecholeminergic polymorphic ventricular tachycardia.

8. The method of Claim 6, wherein the ventricular rhythm disorder is monomorphic ventricular tachycardia.

9. The method of Claim 6, wherein the ventricular rhythm disorder is polymorphic ventricular tachycardia.

10. The method of Claim 6, wherein the cardiac rhythm disorder is ventricular fibrillation.

1 1. The method of Claim 1, wherein the subject has systolic heart failure.

12. The method of Claim 1, wherein the subject has diastolic heart failure.

13. A method of treating arrhythmia in a subject with heart failure, comprising: identifying a subject with arrhythmia and heart failure; and providing said subject a composition comprising a therapeutically effective amount of a compound of formula (I): formula (I)

, or a pharmaceutically acceptable salt, ester, or amide thereof.

14. The method of Claim 13, wherein said heart failure is diastolic heart failure.

15. The method of Claim 13, wherein said heart failure is systolic heart failure.

16. The method of Claim 13, wherein the arrhythmia is an atrial rhythm disorder.

17. The method of Claim 16, wherein the atrial rhythm disorder is atrial fibrillation.

18. The method of Claim 16, wherein the atrial rhythm disorder is atrial flutter.

19. The method of Claim 16, wherein the atrial rhythm disorder is a supraventricular tachycardia.

20. The method of Claim 13, wherein the arrhythmia is a ventricular rhythm disorder.

21. The method of Claim 20, wherein the ventricular rhythm disorder is catecholeminergic polymorphic ventricular tachycardia.

22. The method of Claim 20, wherein the ventricular rhythm disorder is monomorphic ventricular tachycardia.

23. The method of Claim 20, wherein the ventricular rhythm disorder is polymorphic ventricular tachycardia.

24. The method of Claim 20, wherein the cardiac rhythm disorder is ventricular fibrillation.

25. A method of blocking cardiac ion channels in a subject in need thereof, comprising: identifying a subject in need of blockage of one or more cardiac ion channels selected from the group consisting of hERG, hNavl.5, hKvLQTl , hKv4.3, hKvl.5, hCavl .2, hCav3.2, hHCN2, hHCN4, hKir2.1 , hKir3.1, and hKir6.2; and administering to the subject a pharmaceutical composition comprising a therapeutically effective amount a the compound of formula (I): formula (I)

or a pharmaceutically acceptable salt, ester, or amide thereof.

26. The method of Claim 25, wherein the subject has, or is at risk of developing a cardiac rhythm disorder.

27. The method of Claim 26, wherein the cardiac rhythm disorder is an atrial rhythm disorder.

28. The method of Claim 27, wherein the atrial rhythm disorder is atrial fibrillation.

29. The method of Claim 27, wherein the atrial rhythm disorder is atrial flutter.

30. The method of Claim 27, wherein the atrial rhythm disorder is a supraventricular tachycardia.

31. The method of Claim 26, wherein the cardiac rhythm disorder is a ventricular rhythm disorder.

32. The method of Claim 31, wherein the ventricular rhythm disorder is catecholeminergic polymorphic ventricular tachycardia.

33. The method of Claim 31 , wherein the ventricular rhythm disorder is monomorphic ventricular tachycardia.

34. The method of Claim 31, wherein the ventricular rhythm disorder is polymorphic ventricular tachycardia.

35. The method of Claim 31, wherein the cardiac rhythm disorder is ventricular fibrillation.

36. Use of a therapeutically effective amount of a compound having the formula (I), or a pharmaceutically acceptable salt, ester or amide thereof in the manufacture of a medicament for treating or preventing a cardiac rhythm disorder in that has been identified as having or that is at risk of developing a cardiac rhythm disorder: formula (I): formula (I)

37. Use of a therapeutically effective amount of a compound having the formula (I), or a pharmaceutically acceptable salt, ester or amide thereof in the manufacture of a medicament for blocking cardiac ion channels in a subject in need thereof formula (I): formula (I)