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Compounds for treating and preventing exercise-induced cardiac arrhythmias and its preparation method

A compound and halide technology, applied in the field of compound and its preparation for the treatment and prevention of exercise-induced arrhythmia, can solve problems such as not fully elucidating the molecular basis

Inactive Publication Date: 2009-06-24
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Abnormal SR Ca leading to DADs has not been fully elucidated 2+ Molecular Basis of Release

Method used

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  • Compounds for treating and preventing exercise-induced cardiac arrhythmias and its preparation method
  • Compounds for treating and preventing exercise-induced cardiac arrhythmias and its preparation method
  • Compounds for treating and preventing exercise-induced cardiac arrhythmias and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Example 1 - FKBP 12.6-deficient mice

[0158]FKBP 12.6-deficient mice were generated as previously described (Wehrens et al., FKBP12.6 deficiency and defective calcium release channel (ryanodinene receptor) function linked to exercise-induced sudden cardiac death. Cell, 113:829-40, 2003). Briefly, a mouse genomic lambda-phage clone for the murine orthologue of human FK506-binding protein 12.6 (FKBP 12.6) was isolated from the DBA / 1lacJ library using a full-length murine cDNA probe. By replacing 3.5 kb of murine genomic DNA with the PGK-neoselectable marker, a targeting vector was designed to delete exons 3 and 4, which contains the entire coding sequence of murine FKBP 12.6 (Bennett et al., Identification and characterization of the murine FK506 bindingprotein (FKBP) 12.6 gene. Mamm. Genome, 9: 1069-71, 1998). The 5.0-kb 5' fragment and the 1.9-kb 3' fragment were cloned into pJNS2, a backbone vector with PGK-neo and PGK-TK cassettes. DBA / lacJ embryonic stem (ES) ce...

Embodiment 2

[0160] Example 2 - Telemetry recording and locomotor testing of mice

[0161] FKBP 12.6 was maintained and studied according to an experimental design approved by the Institutional Animal Care and Use Committee of Columbia University + / + and FKBP 12.6 - / - mice. Mice were anesthetized using 2.5% isoflurane inhalation anesthesia. ECG radiotelemetry recordings of ambulatory animals were obtained >7 days after intraperitoneal implantation (Data Sciences International, St. Paul, MN) (Wehrens et al., FKBP 12.6 deficiency and defective calcium release channel (ryanodinene receptor) function linked to exercise-induced sudden cardiac death. Cell, 113:829-40, 2003). For the stress test, mice were exercised on an inclined treadmill until exhaustion and then injected intraperitoneally with epinephrine (0.5-2.0 mg / kg) (Wehrens et al., FKBP 12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell, 113:829...

Embodiment 3

[0162] Example 3 - Expression of wild type and RyR2-S2809D mutant

[0163] Mutagenesis of the PKA target site on RyR2 (RyR2-S2809D) was performed as previously described (Wehrens et al., FKBP 12.6 deficiency and defective calcium release channel (ryanodinene receptor) function linked to exercise-induced sudden cardiac death. Cell, 113:829- 40, 2003). Use Ca 2+ For phosphate precipitation, HEK293 cells were co-transfected with 20 μg RyR2 wild-type (WT) or mutant cDNA, and 5 μg FKBP 12.6 cDNA. Vesicles containing RyR2 channels were prepared as previously described (Wehrens et al., FKBP 12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell, 113:829-40, 2003).

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PUM

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Abstract

The present invention provides methods of limiting or preventing decreased levels of RyR2-bound FKBP 12.6 in a patient, methods of treating or preventing exercise-induced cardiac arrhythmias in a patient, and methods of preventing exercise-induced sudden cardiac death in a patient. Use of JTV-519 in these methods is also provided. The present invention also provides a method of identifying a substance for preventing exercise-induced sudden cardiac death, and a substance identified by the method. Also provided are methods of preventing exercise-induced sudden cardiac death by administering these substances. Additionally, the present invention provides methods for the synthesis of JTV-519, radiolabeled JTV-519, and 1,4-benzothiazepine intermediates and derivatives.

Description

[0001] related application [0002] This application is a continuation-in-part of U.S. Patent Application Serial No. 10 / 608,723, filed June 26, 2003, which is a continuation-in-part of U.S. Patent Application Serial No. 10 / 288,606, filed November 5, 2002 A continuation-in-part of U.S. Patent Application Serial No. 10 / 288,606, filed May 10, 2000, of U.S. Patent Application Serial No. 09 / 568,474, issued December 3, 2002 Now US Patent No. 6,489,125 B1, the contents of which are hereby incorporated by reference. [0003] Statement of Government Interest [0004] This invention was made with government support under NIH Grant No. PO1 HL 67849-01. Accordingly, the US Government has certain rights in this invention. Background of the invention [0005] Worldwide, heart failure is a leading cause of mortality and morbidity. In more severe cases of heart failure (New York Heart Association Class IV), the 2-year mortality rate exceeds 50% (Braunwald, E.B., Heart Disease, 4th Edition...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/00G01N33/53A61P9/04A61P9/06A61KG01N33/50G01N33/566G01N33/68
CPCG01N2500/02A61K31/00G01N33/6893G01N2333/912G01N2800/326G01N33/566G01N33/5076G01N33/6887G01N2800/325A61P9/06A61K31/554
Inventor A·R·马克思D·W·兰德里S·X·邓Z·Z·程
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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