Cyclic Amidines Targeting TLR7 8 9 for Autoimmune Treatment
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Solution Overview
Problem
Current therapies for autoimmune diseases like Systemic Lupus Erythematosus (SLE) are inadequate, with existing treatments being either ineffective or associated with significant toxicity and side effects, and there is a need for novel, steroid-free, and non-cytotoxic oral drugs that target Toll-Like Receptors (TLR7, 8, and 9 to manage autoimmune and auto-inflammatory conditions effectively.
Innovation Solution
Development of novel organic compounds that act as antagonists to TLR7, 8, and 9, specifically designed to inhibit these receptors, offering superior antagonism activity, good cytotoxicity, solubility, human microsome stability, and low CYP inhibition, which can be used to treat or prevent SLE and lupus nephritis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If traditional immunosuppressive drugs (e.g., corticosteroids) are used for long-term treatment, then anti-inflammatory effect is achieved, but toxicity and side effects increase
Solution Approach 1:
The invention targets specific segmented pathways (TLR7, TLR8, TLR9) rather than using broad immunosuppression. By dividing the immune response into specific nucleic acid sensing pathways, the treatment achieves anti-inflammatory effects while avoiding the systemic toxicity of traditional immunosuppressants.
Solution Approach 2:
The patent introduces small molecule compounds as intermediaries that selectively bind to and inhibit TLR7/8/9 receptors. These intermediaries mediate the blockade of aberrant nucleic acid sensing without requiring broad immunosuppression, thereby reducing toxicity while maintaining therapeutic efficacy.
2Adaptability or versatility
If biologics (anti-CD20 mAbs, cytokine receptors) are used, then specific immune pathways are targeted, but most clinical studies have failed to show effective results
Solution Approach 1:
The invention replaces large biologic molecules (monoclonal antibodies) with small molecule compounds. This substitution allows for better tissue penetration, oral bioavailability, and potentially lower costs while maintaining specific targeting of TLR7/8/9 pathways through rational drug design.
Solution Approach 2:
The patent employs small molecules with specific physicochemical parameters optimized for TLR7/8/9 binding. By changing the molecular parameters (size, lipophilicity, binding affinity) from large biologics to small molecules, the invention achieves improved pharmacokinetic properties and clinical efficacy in autoimmune diseases.
3Reliability
If TLR7/8/9 inhibition is implemented, then aberrant nucleic acid sensing is blocked, but potential responses to infection may be affected
Solution Approach 1:
The invention applies local quality by selectively inhibiting endosomal TLR7/8/9 pathways where aberrant nucleic acid sensing occurs in autoimmune diseases. The small molecule compounds achieve localized pathway blockade in immune cells while preserving other nucleic acid sensing pathways (such as cytosolic cGAS/STING) that are critical for detecting viral and bacterial infections.
Solution Approach 2:
The patent employs dynamic pathway regulation by selectively modulating TLR7/8/9 signaling without completely abolishing nucleic acid sensing capacity. The small molecules allow for controlled inhibition that can be adjusted to maintain protective immune responses to infections while blocking pathological autoimmunity.
Data Source
AI summary
The present invention relates to compounds of formula (I), wherein R1, R2 and R3 are as described herein, and their pharmaceutically acceptable salt, enantiomer or diastereomer thereof, and compositions including the compounds and methods of using the compounds as antagonist of TLR7 and/or TLR8 and/or TLR9 in the treatment of autoimmune diseases as well as auto-inflammation diseases.