Myosin Modulation for Direct Systolic Dysfunction Treatment
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Solution Overview
Problem
Current medical therapies for systolic heart failure, such as heart failure with reduced ejection fraction (HFrEF), do not effectively address the underlying causal pathways of myocardial dysfunction and are associated with increased mortality due to arrhythmias and ischemia, with no approved therapies targeting the contractile apparatus directly.
Innovation Solution
Oral administration of Compound I, (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide, which acts as a myosin modulator to increase crossbridge formation during cardiac contraction without affecting calcium homeostasis, thereby improving myocardial contractility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current medical therapies for systolic heart failure are used, then heart failure symptoms are managed, but mortality increases due to arrhythmias and ischemia
Solution Approach 1:
The patent extracts the harmful effects of current therapies by identifying that they do not address the underlying causal pathways of myocardial dysfunction. The invention separates the management of symptoms from the treatment of root causes, focusing directly on the contractile apparatus to eliminate arrhythmias and ischemia while improving mortality outcomes.
Solution Approach 2:
The patent introduces a myosin modulator as an intermediary substance that directly targets the contractile apparatus. This mediator increases crossbridge formation between actin and myosin, improving myocardial contractility without the harmful side effects of current therapies. The modulator acts as a bridge between the heart's structural components and the desired functional improvement.
2Reliability
If no approved therapies target the contractile apparatus directly, then current therapies are used, but the underlying causal pathways of myocardial dysfunction are not addressed
Solution Approach 1:
The patent extracts the essential function of the contractile apparatus by focusing solely on the myosin-actin crossbridge interaction. This extraction simplifies the therapeutic mechanism to a direct target approach, eliminating the complexity of current multi-pathway therapies while improving effectiveness at addressing myocardial dysfunction.
Solution Approach 2:
The patent changes the fundamental parameter of myocardial contractility by modulating myosin activity. The myosin modulator alters the crossbridge formation dynamics, transforming the contractile mechanism from a calcium-dependent process to a directly modulated myosin-actin interaction, thereby simplifying the therapeutic approach while improving effectiveness.
3Strength
If myosin modulators are used to increase crossbridge formation, then myocardial contractility improves, but the mechanism becomes more complex
Solution Approach 1:
The patent extracts the core function of myocardial contraction to the myosin-actin crossbridge interaction. By focusing exclusively on this fundamental mechanism and using a myosin modulator to enhance crossbridge formation, the patent simplifies the overall mechanism of action while significantly improving myocardial contractility strength.
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
Compound I safely enhances cardiac function by increasing ejection fraction, reducing cardiovascular mortality and hospitalization risk, and improving exercise capacity and symptoms in patients with systolic heart failure.
Implementation Method 1
Compound I reversibly binds to myosin, increasing the number of myosin/actin crossbridges available to participate in the strongly bound state of the chemomechanical cycle and thereby increasing contraction
Data Source
AI summary
Provided herein are methods, use, and compositions for treating systolic dysfunction such as heart failure with reduced ejection fraction.