Spiro Isobenzofuranazetidine TLR7/8/9 Antagonists for SLE
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current therapies for autoimmune diseases like systemic lupus erythematosus (SLE) are inadequate, with existing treatments being partially effective, toxic, or lacking long-term safety, and there is a need for novel, steroid-free, non-cytotoxic oral drugs that target Toll-Like Receptors (TLR7, 8, and 9) to address autoimmune and auto-inflammatory diseases.
Innovation Solution
Development of novel spiro(isobenzofuranazetidine) compounds that act as antagonists to TLR7, TLR8, and TLR9, inhibiting these receptors to treat autoimmune diseases, particularly SLE, with improved potency and safety profiles compared to existing compounds.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-affected harmful factors
If traditional nonspecific anti-inflammatory or immunosuppressive drugs are used to treat SLE, then broad inflammation and tissue damage are suppressed, but long-term usage causes undesirable toxicity and side effects
Solution Approach 1:
The invention segments the broad immunosuppressive effect into specific targeted effects by designing compounds that selectively antagonize TLR7, TLR8, and TLR9 receptors. This segmentation allows suppression of autoimmune inflammation while preserving other immune functions, thereby reducing toxicity and side effects associated with nonspecific immunosuppressants
Solution Approach 2:
The spiro(isobenzofuranazetidine) compounds act as intermediary substances that specifically bind to and block TLR7/8/9 receptors. These intermediary compounds prevent the harmful interaction between self-nucleic acids and TLRs without causing the broad toxicity of traditional immunosuppressants
2Reliability
If Belimumab is used to treat lupus, then modest therapeutic effect is achieved in a fraction of patients, but the treatment is delayed and only partially effective
Solution Approach 1:
The invention employs preliminary action by blocking TLR7/8/9 receptors upstream in the immune activation pathway, preventing the initiation of autoimmune responses before they fully develop. This upstream blockade achieves faster and more reliable therapeutic effect compared to Belimumab's downstream B-cell targeting approach
3Adaptability or versatility
If other biologics such as anti-CD20 mAbs or cytokine receptor antagonists are used, then specific immune pathways are targeted, but most clinical studies have failed to show effective results
Solution Approach 1:
The spiro(isobenzofuranazetidine) compounds exhibit universality by simultaneously antagonizing multiple TLRs (TLR7, TLR8, and TLR9) with a single molecular structure. This multi-functional approach addresses multiple autoimmune pathways concurrently, providing more reliable clinical efficacy compared to single-target biologics that have failed in clinical studies
Data Source
AI summary
The present invention relates to compounds of formula (I), wherein R1, R3, Y and A are as described herein, and their pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds.