RyCals Compounds Stabilize RyR Channels
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Solution Overview
Problem
Current treatments for disorders and diseases associated with RyR receptors, such as cardiac and skeletal muscular disorders, are inadequate in addressing the maladaptive activation of RyR channels and the resulting calcium leaks, which lead to conditions like heart failure and arrhythmias.
Innovation Solution
Development of novel 1,4-benzothiazepine compounds, referred to as RyCals, that modulate the binding of FKBP proteins to PKA-phosphorylated RyR channels, thereby reducing the open probability of RyR channels and normalizing their function, particularly by increasing the affinity of FKBP12 and FKBP12.6 for PKA-phosphorylated RyR1 and RyR2 channels.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for RyR receptor disorders, then general symptom management is achieved, but maladaptive activation of RyR channels and calcium leaks are not effectively addressed
Solution Approach 1:
The patent employs parameter changes by modifying the chemical structure of benzothiazepine compounds to create novel derivatives with enhanced RyR channel binding affinity. These structural parameter changes result in compounds that specifically target and stabilize the closed state of RyR channels, thereby reducing calcium leaks and addressing the harmful effects that conventional treatments fail to address
Solution Approach 2:
The patent uses FKBP proteins as intermediaries to achieve therapeutic effect. The novel benzothiazepine compounds work by modulating the interaction between FKBP proteins and RyR channels, enhancing FKBP binding to stabilize the closed channel state. This intermediary mechanism allows indirect control of calcium release, effectively reducing calcium leaks without directly targeting the channel itself
2Reliability
If FKBP binding to RyR channels is enhanced to reduce channel open probability, then calcium leaks are reduced, but the complexity of the molecular interaction mechanism increases
Solution Approach 1:
The patent exploits the cell's existing FKBP proteins to achieve therapeutic effect. The novel benzothiazepine compounds enhance the natural binding affinity between FKBP and RyR channels, allowing the cell's own regulatory proteins to perform the stabilizing function. This self-service approach reduces the need for introducing entirely new molecular components, thereby limiting the increase in system complexity while still achieving enhanced channel stability
Data Source
AI summary
The present invention provides novel compounds of Formula Iand salts, hydrates, solvates, complexes, and prodrugs thereof. The present invention further provides methods for synthesizing compounds of Formula I. The invention additionally provides pharmaceutical compositions comprising the compounds of Formula I and methods of using the pharmaceutical compositions of Formula I to treat and prevent disorders and diseases associated with the RyR receptors that regulate calcium channel functioning in cells. Such disorders and diseases include, by way of example only, cardiac disorders and diseases, skeletal muscular disorders and diseases, cognitive disorders and diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome. Cardiac disorder and diseases include, but are not limited to, irregular heartbeat disorders and diseases; exercise-induced irregular heartbeat disorders and diseases; sudden cardiac death; exercise-induced sudden cardiac death; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure. Irregular heartbeat disorders and diseases include and exercise-induced irregular heartbeat disorders and diseases include, but are not limited to, atrial and ventricular arrhythmia; atrial and ventricular fibrillation; atrial and ventricular tachyarrhythmia; atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPVT); and exercise-induced variants thereof. Skeletal muscular disorder and diseases include, but are not limited to, skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence. Cognitive disorders and diseases include, but are not limited to, Alzheimer's Disease, forms of memory loss, and age-dependent memory loss.