Substituted Uracil Compounds for Premature Stop Codon Read-Through
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Solution Overview
Problem
Current pharmacological strategies for promoting translational read-through of premature termination codons in genetic diseases and cystic fibrosis are not optimal in terms of efficacy and safety, necessitating the development of more effective compounds and compositions.
Innovation Solution
Development of substituted uracil compounds and pharmaceutical compositions that can stimulate read-through of premature termination codons, including those associated with cystic fibrosis, Duchenne muscular dystrophy, and other genetic disorders, by modulating the translation process.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If aminoglycosides are used to promote read-through of premature termination codons, then translational read-through is achieved, but toxicity increases and long-term use is not suitable
Solution Approach 1:
The patent applies parameter changes by developing synthetic aminoglycoside derivatives with modified chemical structures (changing molecular parameters) to reduce toxicity while maintaining read-through efficacy. Ataluren represents a further parameter change to a completely different chemical class (small molecule) with improved safety profile for long-term use.
Solution Approach 2:
The patent develops new compounds (ataluren and derivatives) that can be used for long-term treatment without the cumulative toxicity issues of aminoglycosides, effectively replacing short-lived, toxic treatment options with sustainable long-term solutions.
2Ease of operation
If ataluren is used to induce read-through, then oral bioavailability and read-through induction are achieved, but efficacy is reduced in patients using chronic inhaled tobramycin
Solution Approach 1:
The patent identifies and resolves the drug interaction problem by suggesting alternative approaches: using tobramycin intermittently rather than chronically, or using ataluren in patients who cannot tolerate aminoglycosides, effectively inverting the treatment strategy to avoid the harmful interaction while maintaining therapeutic benefit.
3Reliability
If synthetic aminoglycoside derivatives are used, then read-through is improved and toxicity is reduced, but development complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the aminoglycoside structure into modular components that can be independently modified. This allows systematic optimization of each segment to improve read-through efficacy and reduce toxicity separately, then combining them into complete derivative structures.
Solution Approach 2:
The patent systematically changes chemical parameters (molecular weight, charge density, specific functional groups) of aminoglycoside derivatives to optimize the balance between read-through efficacy and toxicity, creating a series of compounds with progressively improved profiles.
Data Source
AI summary
The present disclosure is concerned with substituted uracil compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders associated with the presence of a premature termination codon such as, for example, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer, using the compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.