Anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) and uses thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A01N-043/00
A61K-031/00
출원번호
UP-0809089
(2004-03-25)
등록번호
US-7718644
(2010-06-10)
발명자
/ 주소
Marks, Andrew Robert
Landry, Donald W.
Deng, Shixian
Cheng, Zhen Zhuang
출원인 / 주소
The Trustees of Columbia University in the City of New York
대리인 / 주소
Winston & Strawn LLP
인용정보
피인용 횟수 :
0인용 특허 :
131
초록▼
The present invention provides methods for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject. The present invention further provides methods for treating and preventing atrial and ventricular cardiac arrhythmias, heart failure, and exercise-induced sudden cardiac dea
The present invention provides methods for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject. The present invention further provides methods for treating and preventing atrial and ventricular cardiac arrhythmias, heart failure, and exercise-induced sudden cardiac death in a subject. Additionally, the present invention provides use of JTV-519 in a method for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject who has, or is a candidate for, atrial fibrillation. Also provided are uses of 1,4-benzothiazepine derivatives in methods for treating and preventing atrial and ventricular cardiac arrhythmias and heart failure in a subject, and for preventing exercise-induced sudden cardiac death. The present invention also provides methods for identifying agents for use in treating and preventing atrial fibrillation and heart failure, and agents identified by these methods.
대표청구항▼
What is claimed is: 1. A method for increasing binding of FKBP12.6 to RyR2 in a subject, or limiting a decrease in the level of RyR2-bound FKBP12.6 in a subject, comprising administering an effective amount of an agent to the subject, wherein the agent has the formula: wherein R1=OR′ at
What is claimed is: 1. A method for increasing binding of FKBP12.6 to RyR2 in a subject, or limiting a decrease in the level of RyR2-bound FKBP12.6 in a subject, comprising administering an effective amount of an agent to the subject, wherein the agent has the formula: wherein R1=OR′ at position 7 on the benzothiazepine ring; R′=alkyl; R2=H; R3=H; R4=halide, carboxylic acid, or an alkyl-O— or —S-alkyl-S—; and m=0, 1, or 2. 2. The method of claim 1, wherein the subject is a human. 3. The method of claim 1, wherein the subject has a cardiac condition selected from the group consisting of cardiac arrhythmia, tachycardia, 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. 4. The method of claim 1, wherein the effective amount of the agent is one or more of: (a) from about 5 mg/kg/day to about 20 mg/kg/day, (b) an amount resulting in a plasma concentration of from about 0.02 μM to about 1 μM in the subject, or (c) an amount resulting in a plasma concentration of from about 300 ng/ml to about 1000 ng/ml in the subject. 5. The method of claim 1, wherein the agent is 6. A method for reducing the risk of sudden cardiac death, sustained ventricular tachycardia and non-sustained ventricular tachycardia in a subject, comprising administering an effective amount of an agent to the subject, wherein the agent has the formula: wherein R1=OR′ at position 7 on the benzothiazepine ring; R′ =alkyl; R2=H; R3=H; R4=halide, carboxylic acid, or an alkyl-O— or —S-alkyl-S—; and m=0, 1, or 2. 7. The method of claim 6, wherein the agent is administered to a subject that has or is at risk of developing a condition selected from the group consisting of cardiac arrhythmia, tachycardia, 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. 8. The method of claim 6, wherein the effective amount of the agent is one or more of: (a) from about 5 mg/kg/day to about 20 mg/kg/day, (b) an amount resulting in a plasma concentration of from about 0.02 μM to about 1.0 μM in the subject, or (c) an amount resulting in a plasma concentration of from about 300 ng/ml to about 1000 ng/ml in the subject. 9. The method of claim 6, wherein the agent is 10. The method of claim 6, wherein the subject is a human. 11. The method of claim 1, wherein R4=carboxylic acid and m=0 or 1. 12. The method of claim 1, wherein m=0 or 1. 13. The method of claim 12, wherein R4=carboxylic acid and R′=methyl. 14. The method of claim 13, wherein m=0; and R4=carboxylic acid. 15. The method of claim 6, wherein R4=carboxylic acid and m=0 or 1. 16. The method of claim 6, wherein m=0 or 1. 17. The method of claim 16, wherein R4=carboxylic acid and R′=methyl. 18. The method of claim 17, wherein m=0; and R4=carboxylic acid. 19. A method for treating cardiac arrhythmia in a subject, comprising administering an effective amount of an agent to the subject, wherein the agent has the formula: wherein R1=OR′ at position 7 on the benzothiazepine ring; R′ =alkyl; R2=H; R3=H; R4=halide, carboxylic acid, or an alkyl-O— or —S-alkyl-S—; and m=0, 1, or 2. 20. The method of claim 19, wherein the effective amount of the agent is one or more of: (a) from about 5 mg/kg/day to about 20 mg/kg/day, (b) an amount resulting in a plasma concentration of from about 0.02 μM to about 1 μM in the subject, or (c) an amount resulting in a plasma concentration of from about 300 ng/ml to about 1000 ng/ml in the subject. 21. The method of claim 19, wherein the agent is 22. The method of claim 19, wherein the subject is a human. 23. The method of claim 19, wherein R4=carboxylic acid and m=0 or 1. 24. The method of claim 19, wherein m=0 or 1. 25. The method of claim 24, wherein R4=carboxylic acid and R′=methyl. 26. The method of claim 25, wherein m=0; and R4=carboxylic acid. 27. The method of claim 5, wherein the subject is a human. 28. The method of claim 5, wherein the subject has a cardiac condition selected from the group consisting of cardiac arrhythmia, tachycardia, 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. 29. The method of claim 5, wherein the effective amount of the agent is one or more of: (a) from about 5 mg/kg/day to about 20 mg/kg/day, (b) an amount resulting in a plasma concentration of from about 0.02 μM to about 1.0 μM in the subject, or (c) an amount resulting in a plasma concentration of from about 300 ng/ml to about 1000 ng/ml in the subject.
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Chandrakumar Nizal S. (Vernon Hills IL) Hansen ; Jr. Donald W. (Skokie IL) Peterson Karen B. (Vernon Hills IL) Pitzele Barnett S. (Skokie IL), Substituted dibenzoxazepine and dibenzthiazepine urea compounds, pharmaceutical compositions and methods of use.
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