Direct Cardiac Myosin Modulation for Systolic Dysfunction

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Solution Overview

Problem

There are currently no approved therapies for treating heart failure by targeting the contractile apparatus directly, and existing medical treatments for systolic heart failure, such as inotropic agents, have limitations including increased mortality due to arrhythmias and ischemia, highlighting an urgent need for safe and effective treatments.

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

VSEngineering Contradiction Analysis

1Power

If inotropic agents are used to improve cardiac contractility, then myocardial contractility is enhanced, but mortality increases due to arrhythmias and ischemia

Engineering Contradiction:

Improvemyocardial contractilityVSAvoidmortality rate

Core Design Contradiction:

PowerVSReliability

Solution Approach 1:

The patent applies parameter changes by developing a novel small molecule compound (Formula I) with a specific chemical structure that modulates cardiac myosin activity. This compound represents a parameter change in the therapeutic approach, transitioning from conventional inotropic agents to a new class of myosin modulators that enhance contractility through a different mechanism, thereby improving safety while maintaining efficacy

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent substitutes the mechanical system by replacing conventional inotropic agents (which work through calcium-mediated mechanisms) with a direct myosin modulator. This substitution changes the fundamental mechanism of action from calcium-dependent contractility enhancement to direct myosin-actin interaction modulation, eliminating the arrhythmogenic and ischemic side effects associated with traditional approaches

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

2Adaptability or versatility

If no direct contractile apparatus targeting therapy is available, then current treatments have limitations, but developing new therapies increases research complexity and time

Engineering Contradiction:

Improvetreatment optionsVSAvoidresearch and development complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the complex target (cardiac contractile apparatus) into specific molecular components, namely myosin and its regulatory light chain. By focusing on this segmented target rather than the entire contractile system, the invention enables precise therapeutic intervention through a small molecule that specifically modulates myosin activity, thereby expanding treatment options while managing development complexity

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent introduces an intermediary molecule (Compound I of Formula I) that acts as a mediator between the therapeutic goal and the contractile apparatus. This small molecule serves as an intermediary that binds to myosin and modulates its activity, providing a controllable and reversible mechanism to enhance contractility without directly manipulating the complex contractile machinery, thus facilitating safer and more manageable drug development

Inventive Principle:

Principle #24Intermediary (Mediator)

Data Source

PatentUS20250325531A1Treatment of systolic dysfunction

Publication Date: 2025.10.23 MYOKARDIA INC

AI summary

Provided herein are methods, use, and compositions for treating systolic dysfunction such as heart failure with reduced ejection fraction.