Novel anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) and uses thereof

摘要

Disclosed are 2,3,4,5-tetrahydro-1,4-benzothiazepine derivatives as represented by the general formula (g); wherein R1 is H, OR', SR', N(R')2, alkyl, or halide, at position 6, 7, 8, or 9 on the benzothiazepine ring; R' is H, alkyl, aryl, or acyl; R2 is H, alkyl, alkenyl, or aryl; R3 is H, alkyl, alkenyl, or aryl; R4 is halide, carboxylic acid, or an alkyl containing O or S; and m is 0, 1, or 2. Also disclosed is the use of a compound as defined above for the manufacture of a medicament for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject having a cardiac condition. Also disclosed is the use of a compound as defined above in the manufacture of a medicament for the treatment or prevention of a cardiac condition in a subject (conditions such as cardiac arrhythmia, tachycardia, atrial arrhythmia, atrial tachyarrhythmia, atrial fibrillation, sustained atrial fibrillation, non-sustained atrial fibrillation, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia, sustained ventricular tachycardia, non-sustained ventricular tachycardia, catecholaminergic polymorphic ventricular tachycardia (CPVT), heart failure, sudden cardiac death and exercise-induced sudden cardiac death).