STING Antagonist Urea Derivatives for Potency
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Solution Overview
Problem
There is a need for improved small molecule blockers of the STING protein to address excessive immune system activation associated with various inflammatory diseases and conditions, as existing compounds have low cell-based potency.
Innovation Solution
Development of novel small molecule antagonists of the STING protein, specifically compounds of formula (I), which inhibit STING functional activity by reducing interferon β production, cytokine production, and transcription factor phosphorylation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing small molecule blockers of STING protein are used, then therapeutic benefit is provided, but cell-based potency is low
Solution Approach 1:
The patent applies parameter changes by systematically modifying molecular parameters of STING blockers including core structure variations (pyrimidine, pyridine, triazine rings), substitution patterns (R1-R6 groups), and physicochemical properties to achieve compounds with both high cell-based potency and therapeutic benefit. The optimization of molecular weight, logP, and binding affinity parameters enabled compounds to overcome the low potency limitation of existing blockers.
2Reliability
If STING pathway is activated to fight infection, then immune response is enhanced, but excessive activation causes inflammatory diseases
Solution Approach 1:
The patent employs STING antagonists as intermediary molecules that selectively modulate the STING pathway. These compounds act as mediators between the immune system and pathological conditions, allowing controlled inhibition of excessive STING activation in inflammatory diseases while preserving necessary immune responses. The antagonists provide selective modulation rather than complete blockade, enabling therapeutic intervention in the harmful activation pathway.
Solution Approach 2:
The patent applies inversion by developing compounds that antagonize (inhibit) the STING pathway instead of activating it. While STING activation enhances immune response, the patent inverts this approach by using STING blockers to treat diseases caused by excessive activation, such as interferonopathies and inflammatory conditions. This inverted strategy targets the pathological overactivation rather than the protective immune response.
3Reliability
If small molecule antagonists are developed to inhibit STING, then therapeutic efficacy improves, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the STING antagonist molecules into distinct functional modules: a core heterocyclic structure (pyrimidine, pyridine, or triazine ring) and variable substituent groups (R1-R6). This modular segmentation allows systematic optimization of each module's contribution to potency and selectivity while maintaining overall compound manageability. The segmented approach enabled the identification of key structural features essential for STING binding.
Solution Approach 2:
The patent achieves universality by developing a platform of antagonists based on a common core structure that can be adapted to target STING with high efficacy. The core heterocyclic framework serves multiple functions: binding to STING, providing structural rigidity, and enabling diverse substitution patterns. This universal core approach allows multiple compounds to share the same mechanism of action while achieving therapeutic efficacy across different disease contexts.
Data Source
AI summary
The present invention relates to compounds of formula (I). The compounds maybe used to antagonise the Stimulator of Interferon Genes (STING) protein and may thereby treat liver fibrosis, fatty liver disease, non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, lupus, sepsis, rheumatoid arthritis (RA), type I diabetes, STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutieres syndrome (AGS), familial chilblain lupus (FCL), systemic lupus erythematosus (SLE), retinal vasculopathy, neuroinflammation, systemic inflammatory response syndrome, pancreatitis, cardiovascular disease, renal fibrosis, stroke and age- related macular degeneration (AMD).