Agents for preventing and treating disorders involving modulation of the ryanodine receptors

Abstract

Methods for reducing toxicity or side effects caused by administration of a rycal compound for repairing ryanodine receptor channel leaks when treating a disorder in a subject caused by such leaks. These methods are based upon the selection for administration of those rycal compounds having properties including an EC50 value of 102 nM when assayed for its ability to facilitate the rebinding of FKBP12.6 to PKA-phosphorylated RyR2 or less and less than 50% inhibition of the hERG K+ channel (IKr) when administered at 10 μM to reduce compound toxicity or side effects after administration compared to other rycal compounds not having those properties.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of application 12 / 938,098 filed Nov. 2, 2010, which is a continuation-in-part of (a) U.S. patent application Ser. No. 11 / 506,285, filed Aug. 17, 2006, now U.S. Pat. No. 7,879,840, and (b) a continuation-in-part of U.S. patent application Ser. No. 11 / 809,470 filed Jun. 1, 2007, abandoned. Each of (a) and (b) is a continuation-in-part of U.S. patent application Ser. No. 11 / 212,309, filed Aug. 25, 2005, now U.S. Pat. No. 8,022,058, which is a continuation-in-part of U.S. patent application Ser. No. 10 / 809,089, filed Mar. 25, 2004, now U.S. Pat. No. 7,718,644, which is a continuation-in-part of U.S. patent application Ser. No. 10 / 763,498, filed on Jan. 22, 2004, abandoned. Application (b) also claims the benefit of U.S. Application Nos. 60 / 810,748 filed Jun. 2, 2006 and 60 / 904,348 filed Feb. 28, 2007. The contents of each application mentioned above are expressly incorporated by reference herein.GOVERNMENT I...

AI Technical Summary

Benefits of technology

The patent text describes a new compound that can be used to treat disorders and diseases associated with the regulation of calcium channel functioning in cells. The compound has been found to be effective in repairing leaks in these channels and enhancing the binding of certain proteins to them. The text also describes various methods for using the compound to treat various disorders and diseases, including cardiac, skeletal muscle, cognitive, and memory-related disorders. The technical effect of the patent is to provide a new tool for identifying and developing new treatments for disorders that affect the regulation of calcium channel functioning in cells.

Problems solved by technology

It has been shown that disease forms that result in sustained activation of the sympathetic nervous system and increased plasma catecholamine levels cause maladaptive activation of intracellular stress pathways resulting in destabilization of the RyR1 channel closed state and intracellular Ca2+ leak.

SR Ca2+ leak via RyR1 channels was found to deplete intracellular SR calcium stores, to increase compensatory energy consumption, and to result in significant acceleration of muscle fatigue.

The stress-induced muscle defect permanently reduces isolated muscle and in vivo performance particularly in situations of increased demand.

Despite advances in treatment, heart failure remains an important cause of mortality in Western countries.

Cardiac arrhythmia, a common feature of heart failure, results in many of the deaths associated with the disease.

Atrial fibrillation (AF) is the most common cardiac arrhythmia in humans, and represents a major cause of morbidity and mortality.

In fact, ventricular arrhythmia is the most common cause of sudden death in otherwise-healthy individuals.

This causes marked changes in the biophysical properties of the RyR2 channel, including increased open probability (Po) due to an increased sensitivity to Ca2+-dependent activation; destabilization of the channel, resulting in subconductance states; and impaired coupled gating of the channels, resulting in defective EC coupling and cardiac dysfunction.

Over time, the increased “leak” through RyR2 results in resetting of the SR Ca2+ content to a lower level, which in turn reduces EC coupling gain and contributes to impaired systolic contractility.

This results in depolarizations of the cardiomyocyte membrane known as delayed after-depolarizations (DADs), which are known to trigger fatal ventricular cardiac arrhythmias.

Evidence also suggests that the PKA hyperphosphorylation of RyR2 resulting from beta-adrenergic-receptor activation renders mutated RyR2 channels more likely to open in the relaxation phase of the cardiac cycle, increasing the likelihood of arrhythmias.

Fatigue can result in task failure and it can be a pronounced symptom in a variety of medical conditions including heart failure, renal failure, cancer, and various muscular dystrophies.

It is evident, then, that a defect in excitation-contraction coupling that resulted in a reduction in the amplitude of the Ca2+ transient would, among other effects, result in impaired contraction and force generation through ineffective myosin cross bridge formation.

It has therefore been proposed that RyR1 Ca2+ leak limits peak muscle performance and mediates muscle damage during prolonged, stressful exercise.

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