Piperidine Urea Compounds for DCM Contractility Without Systolic Delay
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Solution Overview
Problem
Current treatments for dilated cardiomyopathy (DCM) are inadequate in addressing the progressive nature of the disease, leading to high morbidity and mortality, with a need for improved therapeutic agents to enhance cardiac function and reduce hospitalizations.
Innovation Solution
Development of 4-methylsulfonyl-substituted piperidine urea compounds that increase myocardial contractility by enhancing phosphate release from myosin without prolonging systole or shortening diastole, thereby improving systolic function in patients with DCM.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current standard treatments (beta-blockers, ACE inhibitors, ARBs, mineralcorticoid receptor blockers, loop diuretics) are used for DCM, then heart failure symptoms can be managed, but morbidity and mortality remain high and hospitalization for heart failure is the most common reason for hospitalization in the elderly
Solution Approach 1:
The patent applies parameter changes by developing novel chemical compounds with specific molecular structures (Formula I) that target cardiac myosin binding. These compounds represent a fundamental change in the pharmacological parameter of cardiac contractility modulation, moving from standard heart failure management to direct enhancement of myocardial contraction through selective myosin binding, thereby improving both treatment reliability and patient quality of life
2Reliability
If implantable cardioverter defibrillators (ICD) and cardiac resynchronization therapy (CRT) are used, then sudden arrhythmic death and heart failure-free survival can be improved, but these are invasive interventions with high morbidity and mortality remaining
Solution Approach 1:
The patent applies mechanics substitution by replacing invasive mechanical devices (ICD and CRT) with a pharmacological approach. The novel compounds work through biochemical mechanisms to improve cardiac function, substituting the need for complex mechanical intervention systems with a molecular-level therapeutic action that directly enhances cardiac contractility and survival without surgical implantation
3Power
If new therapeutic agents are developed to improve cardiac function, then systolic function can be enhanced, but the compounds must not prolong systole or shorten diastole
Solution Approach 1:
The patent applies local quality by designing compounds that act specifically on the myosin binding site in cardiac muscle cells, producing a localized effect on contractility without global disruption of the cardiac cycle timing. The selective binding to cardiac myosin allows enhancement of systolic power while preserving the normal duration and sequence of cardiac phases through targeted molecular interaction rather than systemic physiological disruption
Data Source
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Figure 1E
AI summary
The present invention provides novel 4-methylsulphone-substituted piperidine urea compounds that are useful for the treatment of dilated cardiomyopathy (DCM) and conditions associated with left and/or right ventricular systolic dysfunction or systolic reserve. The synthesis and characterization of the compounds is described, as well as methods for treating DCM and other forms of heart disease.