Piperidine Urea Inotropes That Boost Contractility Without Calcium Overload
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Solution Overview
Problem
Current treatments for heart failure, particularly those aimed at increasing heart contractility, often cause adverse effects such as increased calcium concentrations, leading to issues like myocardial oxygen demand, ischemia, arrhythmia, and excessive hypotension, without effectively addressing the underlying pathology of reduced heart contractility.
Innovation Solution
Development of piperidine urea derivatives that enhance cardiomyocyte sarcomere sensitivity to existing calcium levels, rather than increasing calcium concentrations, thereby providing a safe and effective inotropic effect without the common side effects of traditional inotropic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Strength
If traditional inotropic agents (PDE3-inhibitors, adrenergic agonists) are used to increase heart contractility, then heart contractility is improved, but adverse effects occur including increased calcium concentrations, myocardial oxygen demand, ischemia, arrhythmia, and excessive hypotension
Solution Approach 1:
The patent changes the mechanism parameter from increasing calcium concentrations to enhancing sarcomere calcium sensitivity. The piperidine urea derivatives act on the calcium-binding sites of troponin C, increasing the affinity of calcium binding without altering intracellular calcium levels. This parameter change resolves the contradiction by achieving improved contractility through a different biochemical pathway that does not trigger the harmful cascade of traditional inotropes.
Solution Approach 2:
The patent substitutes the mechanical/chemical system of calcium concentration increase with a molecular interaction system targeting troponin C. Instead of using agents that increase cytosolic calcium (which trigger adverse effects), the invention uses piperidine urea derivatives that directly modulate the calcium-sensing mechanism of the sarcomere, replacing the harmful mechanism with a targeted molecular interaction that achieves the same functional outcome without the side effects.
2Strength
If calcium concentrations are increased to strengthen heart contractions, then inotropic effect is achieved, but troponin levels rise indicating tissue damage and poor prognosis
Solution Approach 1:
The patent changes the inotropic mechanism from calcium concentration increase to calcium sensitivity enhancement. By targeting troponin C binding affinity rather than calcium release, the invention achieves contractile enhancement without the calcium overload that causes myocardial injury and troponin release. This parameter change eliminates the harmful feedback loop where increased calcium leads to cell damage and troponin leakage.
3Strength
If conventional inotropic treatments are applied to address reduced heart contractility in heart failure, then short-term contractility improvement occurs, but underlying pathology of reduced contractility remains unaddressed and adverse effects accumulate
Solution Approach 1:
The patent substitutes the harmful mechanical system of calcium overload with a targeted molecular modulation system. The piperidine urea derivatives specifically bind to troponin C and enhance calcium binding affinity, creating a selective and controllable mechanism that improves contractility without the non-specific adverse effects of traditional inotropes. This substitution provides a safer, more reliable treatment with better long-term tolerability.
Data Source
AI summary
The invention concerns the use of compounds represented by formula (I)as inotropic agents. The compounds of formula (I), which include, as preferred, 1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-methyl-3,3-dimethyl-4-piperidyl]-urea and its hydrochloride salt, are herein reported to have a significant inotropic activity on cardiomyocytes from both normal and myocardial infarction-induced heart failure animal models, which makes them useful for treating cardiovascular patients in need thereof. Differently from known inotropic agents, the present compounds are effective on cardiomyocyte contractility without influencing calcium mobilization. Accordingly, they are advantageously free from adverse effects caused by increased calcium concentrations, such as increased oxygen demand, tachycardia, arrhythmia, ischemia, etc. Overall, a new, safe and effective inotropic treatment is thus made available.