Fast Skeletal Muscle Myosin Inhibitors for Selective Contractility Control
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for neuromuscular diseases such as tremor, spasticity, muscular dystrophy, and multiple sclerosis are limited and often cause significant neurological and cardiovascular side effects due to off-target effects, necessitating the development of compounds that selectively modulate skeletal muscle contractility through new mechanisms of action.
Innovation Solution
Development of heterocyclic compounds, including indane and coumaran derivatives, which act as fast skeletal muscle myosin inhibitors, offering a new mechanism to treat neuromuscular diseases by selectively modulating muscle contractility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapeutics are used to treat neuromuscular diseases, then some therapeutic effect is achieved, but significant neurological and cardiovascular side effects occur due to off-target effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula I with defined substituents R1-R7, A, B, X) that confer selective affinity for skeletal muscle myosin over other myosin isoforms. The structural features including the indane/coumaran core, heteroaryl groups, and specific substitution patterns create localized interaction characteristics that enable selective binding to the target protein in skeletal muscle tissue while minimizing interactions with cardiac or smooth muscle myosin, thereby reducing off-target side effects
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters such as the heteroaryl group type (pyridyl, pyrimidinyl, triazinyl), substitution patterns (fluoro, chloro, methyl groups), and linker configurations in Formula I compounds. These parameter variations optimize the compound's selectivity profile and binding affinity, allowing fine-tuning of the therapeutic effect while minimizing adverse interactions with non-target proteins
2Adaptability or versatility
If available therapeutics are used for neuromuscular diseases, then treatment is provided, but the treatment options are severely limited and therapeutic index is poor
Solution Approach 1:
The patent applies segmentation by dividing the molecular structure into distinct functional segments: the core indane or coumaran structure (Formula I), various heteroaryl substituents (A), and specific side chain configurations (R1-R7). This modular design allows independent optimization of each segment for selectivity and activity, enabling the development of multiple compound variants with improved therapeutic indices for different neuromuscular conditions
Solution Approach 2:
The patent achieves universality by designing a platform compound (Formula I) that can treat multiple neuromuscular diseases including tremor, spasticity, muscular dystrophy, and multiple sclerosis through a common mechanism of action (skeletal muscle myosin inhibition). The versatile molecular scaffold can be adapted to address different pathological conditions, expanding treatment options while maintaining a favorable therapeutic index across multiple indications
Data Source
AI summary
Provided are compounds of Formula (I). Also provided is a pharmaceutically acceptable composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Also provided are methods of using a compound of Formula (I), or a pharmaceutically acceptable salt thereof.