Heterocyclic Amide Splicing Modulators for Neurodegenerative Disease
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Solution Overview
Problem
Current approaches to treating diseases associated with alternative splicing, such as neurodegenerative and repeat expansion diseases, face challenges including unfavorable pharmacokinetics, limited oral administration, and ineffective tissue delivery, particularly for the brain. Additionally, existing small-molecule splicing modulators are limited in chemical diversity.
Innovation Solution
Development of novel small molecule splicing modulators (SMSMs) that target specific cis-elements in RNA transcripts, including splice sites, branch points, splicing enhancers, or silencers. These SMSMs can alter the sequence or abundance of mature transcripts, potentially affecting protein function or RNA function in non-coding transcripts.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oligonucleotide-based therapeutics are used to treat splicing diseases, then splicing modulation can be achieved, but pharmacokinetics are unfavorable and tissue delivery is ineffective
Solution Approach 1:
The patent transitions from oligonucleotide-based therapeutics to small-molecule compounds, fundamentally changing the physical and chemical parameters of the therapeutic agent. This parameter change enables improved pharmacokinetics, oral bioavailability, and tissue penetration while maintaining splicing modulation capability through alternative molecular mechanisms
2Quantity of substance
If current small-molecule splicing modulators are used, then excellent pharmacokinetics and bioavailability are achieved, but chemical diversity is limited
Solution Approach 1:
The patent employs a library of 20 distinct small-molecule compounds, each representing a different chemical series or structural class. This segmentation approach diversifies the chemical strategies for splicing modulation while maintaining the advantageous pharmacokinetic properties of small molecules
Solution Approach 2:
The patent utilizes compounds from multiple chemical series (including but not limited to heterocyclic structures, aromatic compounds, and various functional group combinations), creating a composite therapeutic approach that leverages the strengths of different chemical architectures to achieve splicing modulation
3Reliability
If CRISPR-based genome editing or virus-aided gene therapy is used, then genetic correction can be achieved, but technical and clinical challenges remain
Solution Approach 1:
The patent replaces complex genetic editing mechanisms (CRISPR-Cas systems, viral vectors) with small-molecule chemical compounds that directly modulate splicing. This substitution eliminates the need for complex delivery systems, reduces immunogenicity concerns, and simplifies clinical implementation while achieving functional correction through splicing modulation rather than permanent genetic alteration
Data Source
AI summary
The present disclosure relates to compounds of Formula (I), and subformulas thereof, and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds of the present disclosure may act as small molecule splicing modulator compounds that modulate splicing of mRNA, such as pre-mRNA, encoded genes, and methods of use of the compounds for modulating splicing and treating related diseases and conditions. The compounds disclosed herein may possess activity toward various genetic pathways and are accordingly useful in methods of treatment of diseases or disorders of the human or animal body.