Androstane SERCA2a Activators for Selective Heart Failure Therapy
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for heart failure, particularly acute heart failure, lack effective oral compounds that can selectively activate SERCA2a to improve cardiac function while minimizing arrhythmogenic risks and are not optimally absorbed for chronic administration.
Innovation Solution
Development of androstane derivatives that predominantly or purely activate SERCA2a with minimal Na+/K+ ATPase pump inhibition, featuring specific functional groups at C3, C6, and C7 positions, allowing for oral administration and improved cardiac function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current inotropic agents (dobutamine, levosimendan) are used to improve cardiac contractility, then cardiac function is improved, but arrhythmogenic risks and myocardial oxygen consumption increase
Solution Approach 1:
The patent segments the cardiac function improvement into two distinct mechanisms: SERCA2a activation for calcium reuptake enhancement and selective avoidance of Na+/K+ ATPase inhibition. This segmentation allows improving cardiac contractility and relaxation without triggering the harmful arrhythmogenic effects associated with non-selective inotropic agents.
Solution Approach 2:
The androstane derivative compounds act as intermediaries that selectively activate SERCA2a without significantly inhibiting Na+/K+ ATPase. This intermediary action provides a safer pathway for improving cardiac function by mediating calcium handling improvement without the harmful side effects of conventional inotropes.
2Reliability
If SERCA2a is activated to improve calcium uptake, then cardiac relaxation is improved, but selectivity must be maintained to avoid Na+/K+ ATPase inhibition
Solution Approach 1:
The patent applies local quality by designing compounds with specific functional group configurations at C3, C6, and C7 positions that create localized molecular properties for selective SERCA2a binding. This local molecular design ensures high selectivity for SERCA2a activation while minimizing interaction with and inhibition of Na+/K+ ATPase.
Solution Approach 2:
The patent utilizes parameter changes by systematically varying the functional groups at specific positions (C3, C6, C7) of the androstane core structure. These parameter changes in molecular structure directly influence the selectivity profile, enabling optimization for pure SERCA2a activation with minimal Na+/K+ ATPase inhibition.
3Duration of action of stationary object
If oral compounds are developed for chronic heart failure treatment, then chronic administration is enabled, but absorption and bioavailability must be optimized
Solution Approach 1:
The patent applies parameter changes by modifying physicochemical properties of the androstane derivatives, including functional group selection and molecular weight optimization, to achieve optimal oral absorption and bioavailability. These parameter adjustments enable the compounds to be suitable for chronic oral administration in heart failure patients.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The androstane derivatives enhance SERCA2a activity, improving cardiac relaxation and contraction, reducing arrhythmogenic risks, and providing a viable oral treatment option for heart failure.
Implementation Method 1
androstane derivatives with activity as pure or predominantly pure stimulators of SERCA2a
Data Source
AI summary
Compounds and compositions for the activation of SERCA2a are disclosed. In particular, provided are compounds that act as predominantly pure or pure SERCA2a activators while only moderately inhibiting the Na+/K+ ATPase. In general, the disclosed compounds are derivatives of androstane having the formula (I). Also disclosed herein are pharmaceutical compositions comprising one or more of the compounds of formula (I) for use for the treatment of heart failure.