Atrial fibrillation is one of the most general arrhythmia in clinical stages wherein an irregular and frequent excitation of atrium stops a series of contraction and expansion as an auxiliary pump of atrium, and particularly, an incidence thereof increases with advancing age. Atrial fibrillation is not a fetal arrhythmia, but worsens heart functions and is known to cause a complication such as congestive heart failure, thromboembolism, ventricular fibrillation, etc.
Antiarrhythmic agents placed on the market until now have been developed as therapeutic agents for ventricular arrhythmia and atrial or supraventricular arrhythmia. Malignant ventricular arrhythmia immediately threatens life and requires emergency treatment, and a class Ia (e.g., procainamide, quinidine), a class Ic (e.g., flecainide, propafenone) or a class III (e.g., dofetilide, amiodarone) agent has been used in drug treatment of ventricular arrhythmia. It has been reported that these class I and class III agents prevent a recurrence of atrial fibrillation (Nonpatent Document 1). However, they have potentials to increase mortalities due to their potentially lethal ventricular arrhythmogenic activities (Nonpatent Documents 2 to 4).
Since atrial fibrillation shortens cardiac action potential duration (APD), an APD-prolonging agent may be a therapeutic agent for atrial fibrillation in theory. A prolongation of cardiac APD is caused by increasing inward currents (i.e., Na+ or Ca2+ currents which are referred to as INa or ICa, respectively, hereinafter) or decreasing outward currents of repolarized potassium K. Delayed rectifier (IK) K+ currents are main outward currents involved in a repolarization process of action potential, and transient outward currents (Ito) and inward rectifier (IK1) K+ currents relate to an initial phase and a terminal phase of the repolarization, respectively. In cellular electrophysiological study, IK comprises two subtypes of pharmacologically and kinetically different K+ currents, i.e., IKr (rapid activation) and IKs (delayed activation) (Nonpatent Document 5).
Dofetilide, a class III antiarrhythmic agent, shows an antiarrhythmic activity by blocking IK, which is an IK rapid activating ingredient and exists in human atrium and ventricle (Nonpatent Document 1). Since an IK, blocker prolongs APD and a refractory period both in atrium and ventricle without affecting conduction itself, it has potentials to be an agent useful in the treatment of arrhythmia such as atrial fibrillation in theory (Nonpatent Document 4). However, it has been reported that said blocker has an arrhythmogenic activity and develops polymorphic torsades de pointes (Nonpatent Document 6).
In contrast, it has been reported that amiodarone has a class III property (Nonpatent Documents 7 and 8). However, since it has various activities on multiple ion channels and is not a selective class III agent, a usage thereof has been strictly limited in terms of adverse effects thereof (Nonpatent Documents 9 to 11). Accordingly, currently available agents such as amiodarone and dofetilide have potentially lethal serious adverse effects such as ventricular arrhythmogenic activities, and hence, a high safe agent with beneficial efficacy has been desired.
Recently, super rapid activated delayed rectifier L+ currents (IKur) which are prolonged outward currents have been identified in human atrial myocyte. IKur specifically exists in atrium, not in human ventricle. A molecular correlation of IKur in human atrium is potassium channel referred to as Kv 1.5, and Kv 1.5 mRNA (Nonpatent Document 12) and protein (Nonpatent Document 13) have been detected in human atrial tissues. It has been believed that IKur widely contributes to a repolarization in human atrium due to a rapid activation and a delayed inactivation thereof. Therefore, it would appear that since a compound having an IKur blocking activity prolongs a refractory in atrium without delaying a ventricular repolarization and prolonging a refractory period in ventricle, it may resolve adverse effect problems such as an arrhythmia-induced QT extension syndrome after a depolarization found in the current class III agents (Nonpatent Documents 14 and 15).
In contrast, it has been shown that a reentry (reciprocation) is a remarkable mechanism which causes a supraventricular arrhythmia in human (Nonpatent Document 16). Specifically, reciprocations occur at random in different locations in atrium, and atrial fibrillation is caused by several times of repetitions of electrical excitations by a single stimulation. Accordingly, an increase of myocardial refractory by a prolongation of cardiac APD prevents and/or stops reentry arrhythmia Additionally, since cardiac APD depends on contributions of potassium currents IKr, IKs, IKur which relate to a repolarization phase and transient outward currents Ito, it is desired that a blocker which acts on any one of these currents prolongs action potential duration and produces an antiarrhythmic effect.
Patent Document 1 discloses useful indazole derivatives as a SGK-1 inhibitor, but the document does not disclose any IKur blocking activities.
[Patent Document 1] WO2005/011681
[Nonpatent Document 1] Circulation, 102:2665-2670
[Nonpatent Document 2] Am. J. Cardiol., 65:20 B-29B, 1990
[Nonpatent Document 3] Lancet, 348:7-12, 1996
[Nonpatent Document 4] Expert Opin. Invest. Drugs, 9:2695-2704, 2000
[Nonpatent Document 5] J. Gen. Physiol. 1990, 96:195-215
[Nonpatent Document 6] Am. J. Cardiol., 72:44B-49B, 1993
[Nonpatent Document 7] Br. J. Pharmacol., 39:675-687, 1970
[Nonpatent Document 8] Br. J. Pharmacol., 39:657-667, 1970
[Nonpatent Document 9] J. Am. Coll. Cardiol., 20:1063-1065, 1992
[Nonpatent Document 10] Circulation, 104:2118-2150, 2001
[Nonpatent Document 11] A. Curr. Opin. Pharmacol. 2:154-159, 2002
[Nonpatent Document 12] Basic Res. Cardiol., 97:424-433, 2002
[Nonpatent Document 13] J. Clin. Invest., 96:282-292, 1995
[Nonpatent Document 14] J. Med. Chem., 46:486-498, 2003
[Nonpatent Document 15] Naunyn-Schmedieberg's Arch. Pharmacol., 366:482-487, 2002
[Nonpatent Document 16] Nature, 415:219-226, 2002
USPTO Backgrounds
USPTO Backgrounds