I-491 Polymorphs for Myosin-Driven Contractility
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for heart failure, particularly non-ischemic dilated cardiomyopathy (DCM) and heart failure with reduced ejection fraction (HFrEF), do not effectively target the underlying myocardial dysfunction, leading to high morbidity and mortality, and there is a need for safe and effective therapies that improve systolic function.
Innovation Solution
Development of polymorphic forms of (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide (I-491) that enhance phosphate release from myosin without prolonging systole or shortening diastole, thereby improving systolic function in patients with DCM or HFrEF.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for heart failure are used, then they are administered to patients, but they do not effectively target the underlying myocardial dysfunction, leading to high morbidity and mortality
Solution Approach 1:
The patent employs parameter changes by developing polymorphic forms of compound I-491 with specific crystal structures (Forms A, B, C, D) that optimize pharmacokinetic and pharmacodynamic properties. The polymorphic forms exhibit different solubility, stability, and bioavailability characteristics, allowing selection of the most effective form for treating myocardial dysfunction while minimizing adverse outcomes
Solution Approach 2:
The invention applies local quality by designing the compound with specific molecular features including a piperidine ring, isoxazole substituent, and difluoromethylpyrazole group that locally interact with myocardial targets. The compound specifically targets cardiac myosin to enhance phosphate release and improve systolic function without affecting other organ systems
2Reliability
If polymorphic forms of I-491 are used to increase contractility, then systolic function is improved, but the complexity of developing and characterizing multiple polymorphs increases
Solution Approach 1:
The patent segments the complex polymorph characterization into distinct, analyzable components by defining specific X-ray powder diffraction patterns for each polymorphic form (Forms A, B, C, D). Each form is characterized by unique diffraction peaks at specific 2-theta angles, allowing systematic identification and quality control without requiring comprehensive analysis of all possible crystal structures
Solution Approach 2:
The invention uses parameter changes by establishing specific diffraction peak parameters (2-theta angles, intensity ratios) that define each polymorphic form. These parameter specifications simplify the characterization process by providing clear, measurable criteria for identifying the correct polymorph and ensuring batch-to-batch consistency
Data Source
AI summary
The present invention provides novel polymorphs of (R)-4-(1-((3-(difluoromethyl)-1-methyl-1H-pyrazol-4-yl)sulfonyl)-1-fluoroethyl)-N-(isoxazol-3-yl)piperidine-1-carboxamide (I-491) that are useful for the treatment of cardiac disorders including systolic dysfunction, dilated cardiomyopathy (DCM), heart failure with reserved ejection fraction (HFrEF), and conditions associated with left and/or right ventricular systolic dysfunction or systolic reserve. The synthesis and characterization of the polymorphs is described, as well as methods for treating systolic dysfunction, DCM, HFrEF, and other forms of heart disease.