SMN2 Splicing Modulator Compounds for Exon 7 Inclusion in SMA
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Solution Overview
Problem
Current treatments for spinal muscular atrophy (SMA) are limited to supportive care and lack drugs that address the underlying cause of the disease, with existing therapeutic approaches showing toxicity or safety concerns, and there is a need for compounds that can alter the course of SMA.
Innovation Solution
Development of compounds that modulate SMN2 gene splicing to increase the inclusion of exon 7 in RNA transcripts, potentially enhancing SMN protein production and improving motor neuron function.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If supportive care is provided for SMA patients, then patient comfort and symptom management are improved, but the underlying cause of the disease is not addressed and life expectancy remains limited
Solution Approach 1:
The patent identifies and exploits the alternative splicing mechanism of the SMN2 gene, which normally produces non-functional truncated SMN protein, and converts this harmful effect into a beneficial therapeutic target. By using splicing modulators to shift the splicing pattern toward inclusion of exon 7, the disease-causing alternative splicing is transformed into a therapeutic opportunity to produce functional SMN protein.
Solution Approach 2:
The patent applies parameter changes by modifying the splicing pattern of SMN2 pre-mRNA through splicing modulators. These compounds alter the biochemical parameters of RNA processing to increase the proportion of fully spliced, functional SMN2 transcripts, thereby changing the functional output of the gene from non-functional to functional protein production.
2Reliability
If existing therapeutic approaches are used to address SMA, then some therapeutic effect is achieved, but toxicity or safety concerns arise
Solution Approach 1:
The patent introduces splicing modulators as intermediary substances that mediate between the SMN2 gene and the desired therapeutic outcome. These modulators act as selective agents that influence the splicing process without directly interfering with other cellular functions, thereby achieving therapeutic effect while minimizing toxicity compared to broader-spectrum treatments.
3Quantity of substance
If SMN2 gene splicing is modulated to increase exon 7 inclusion, then SMN protein production is enhanced, but the complexity of the therapeutic compound structure increases
Solution Approach 1:
The patent employs parameter changes in the chemical structure of splicing modulators to optimize their biological activity. By systematically varying molecular parameters such as functional groups, steric properties, and electronic characteristics, the patent identifies structural features that enhance exon 7 inclusion efficiency while maintaining reasonable structural complexity for pharmacological development.
Data Source
AI summary
The present invention provides compounds of formula (I)wherein A, R1, R2 and R3 are as described herein, as well as pharmaceutically acceptable salts thereof. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as medicaments.