Indazole Macrocycle STING Antagonists for Autoimmune Inflammation
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Solution Overview
Problem
Current treatments for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel diseases are inadequate, offering only symptomatic relief with significant side effects and limited remission, and there is a need for pathway-selective agents that target the STING pathway to manage chronic inflammation and associated disorders.
Innovation Solution
Development of novel indazole macrocycle compounds that act as STING antagonists to modulate the STING pathway, providing therapeutic benefits for autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, and certain types of cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If steroid and broad immunosuppressant drugs are used for treatment, then symptomatic relief is achieved, but treatment-related toxicity increases
Solution Approach 1:
The patent changes the therapeutic parameter from broad immunosuppression to pathway-selective STING inhibition. The indazole macrocycle compounds specifically target the STING pathway while sparing other immune functions, thereby maintaining therapeutic efficacy while reducing off-target toxicity associated with conventional immunosuppressants
Solution Approach 2:
The patent introduces STING antagonists as intermediary agents that selectively block the STING pathway. These compounds act as mediators between the immune system and inflammatory responses, providing pathway-specific modulation without the broad suppression caused by traditional drugs
2Reliability
If pathway selective agents are used, then specific immune pathway blockade is achieved, but infection risk increases
Solution Approach 1:
The patent refines the selectivity parameter by targeting STING specifically within the cGAS-STING pathway. This precise pathway selection allows blockade of pathogenic signaling while preserving other immune functions including antimicrobial defense, thereby reducing infection risk compared to broader immunosuppressants
3Reliability
If Belimumab is used for SLE treatment, then FDA approval is obtained, but onset of remission is slow with modest efficacy
Solution Approach 1:
The patent changes the kinetic parameter of drug action by targeting upstream STING pathway activation. The indazole macrocycle compounds produce rapid and potent STING inhibition, leading to faster onset of remission compared to Belimumab's modest and slow efficacy
Solution Approach 2:
The patent applies preliminary blockade of STING pathway activation before full inflammatory cascade development. By inhibiting STING upstream in the signaling pathway, the compounds prevent subsequent inflammatory mediator production, achieving faster clinical response
4Ease of manufacture
If conventional treatments are used, then current standard of care is maintained, but quality of life with chronic inflammation deteriorates
Solution Approach 1:
The patent transforms the therapeutic parameter from symptomatic management to pathway-selective disease modification. The STING antagonists address the underlying pathogenic mechanism, providing superior quality of life improvement compared to conventional symptomatic treatments
Data Source
AI summary
The present invention relates to compounds of formula (Ia), (Ia), wherein R1 to R3, Q1, Q2, A1 to A6 are as described herein, and their pharmaceutically acceptable salt thereof, and compositions including the compounds and methods of using the compounds.