Hetaryl-Substituted Indazoles and Benzimidazoles for STING Inhibition
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Solution Overview
Problem
Current STING receptor inhibitors face challenges such as difficulty in binding to the ligand binding pocket, poor cellular membrane permeability, metabolic instability, and interactions with co-administered drugs, leading to potential adverse effects on patient metabolism and detoxification processes.
Innovation Solution
Development of heteraryl substituted indazoles and benzimidazoles that optimize binding to the STING receptor, enhance cellular membrane permeability, and minimize interactions with cytochrome P450 enzymes, ensuring good metabolic stability and reduced cytotoxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current STING receptor inhibitors are used, then STING activity is inhibited, but cellular membrane permeability is poor
Solution Approach 1:
The patent modifies chemical parameters of the inhibitor molecules by introducing heteraryl substituents at specific positions (R1, R2, R3) of the core structure, optimizing the balance between STING binding affinity and membrane permeability through systematic structural variation
2Reliability
If current STING receptor inhibitors are used, then STING activity is inhibited, but metabolic stability is poor
Solution Approach 1:
The patent optimizes metabolic stability by selecting specific heteraryl groups (such as pyridyl, pyrimidinyl, triazinyl) and substituent patterns that resist metabolic degradation while preserving STING binding capability, addressing the poor metabolic stability of current inhibitors
Solution Approach 2:
The patent creates composite molecular structures combining a core scaffold with various heteraryl substituents, where the combination provides both STING inhibition activity and improved metabolic stability that neither component alone would achieve
3Reliability
If current STING receptor inhibitors are used, then STING activity is inhibited, but interactions with cytochrome P450 enzymes occur, leading to adverse effects on patient metabolism and detoxification processes
Solution Approach 1:
The patent extracts or removes the problematic interaction with cytochrome P450 enzymes by designing molecules with specific heteraryl substituents that avoid P450 binding sites, thereby eliminating the harmful metabolic interactions while preserving the desired STING inhibition
Data Source
AI summary
This invention relates to compounds of formula (1)and their use in the prevention, delaying and/or treatment of diseases or conditions which can be influenced by STING inhibition.