Cardiac Myosin Polymorphs for Selective and Stable Formulation
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Solution Overview
Problem
Current cardiac sarcomere-targeting agents for treating conditions like hypertrophic cardiomyopathy and heart failure with preserved ejection fraction are poorly selective, leading to adverse effects and limited therapeutic index, necessitating the development of more selective and stable formulations.
Innovation Solution
Development of polymorphic forms of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde (compound 1) with improved stability and selectivity for cardiac myosin, reducing impact on smooth muscle myosin and enhancing therapeutic index.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current cardiac sarcomere-targeting agents are used to treat cardiac diseases, then contractility can be increased, but selectivity is poor leading to adverse effects and limited therapeutic index
Solution Approach 1:
The patent applies local quality by designing compound 1 with specific molecular features that confer selective binding to cardiac myosin. The compound's structure includes a cyclohexyl ring and spirocyclic framework that enable preferential interaction with cardiac myosin over smooth muscle myosin, achieving local selectivity at the target site while minimizing off-target effects on smooth muscle tissue.
Solution Approach 2:
The patent employs parameter changes by modifying the molecular parameters of the therapeutic agent. Compound 1 exhibits altered binding affinity parameters compared to conventional inotropes, with selective inhibition of cardiac myosin ATPase activity while showing minimal effect on smooth muscle myosin, thereby improving the therapeutic index through optimized molecular parameters.
2Stability of the object's composition
If polymorphic forms of compound 1 are developed, then stability and selectivity are improved, but manufacturing complexity increases
Solution Approach 1:
The patent addresses polymorph stability by characterizing and controlling the crystalline phase transitions of compound 1. The patent identifies specific polymorphic forms with enhanced stability profiles and establishes controlled crystallization conditions to produce the desired polymorph, thereby managing stability while providing a framework for controlled manufacturing.
Data Source
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AI summary
Provided herein are crystalline forms of 5-(3,4-difluorobenzyl)-8-((1r,4r)-4-methylcyclohexyl)-6,9-dioxo-2,5,8-triazaspiro[3.5]nonane-2-carbaldehyde, compositions thereof, methods of preparation thereof, and methods of their uses.