RORα/γt Modulator Compounds for Targeted Cytokine Control
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Solution Overview
Problem
Current treatments for autoimmune diseases and antibody-mediated allograft rejection lack efficacy due to the lack of understanding of molecular pathways involving RORγt, and existing modulators for RORs are not sufficiently effective.
Innovation Solution
Development of novel compounds represented by Formula (I), (II), (III), and (IV) that act as modulators of RORα and RORγt, specifically targeting these receptors to control autoimmune diseases and antibody-mediated rejection by inhibiting or activating their activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments (NSAIDs and immunosuppressants) are used for autoimmune diseases, then symptoms are improved, but the disease is not cured and efficacy is limited
Solution Approach 1:
The patent changes the molecular target parameter from general immune suppression to specific RORγt receptor modulation. The compounds selectively bind to and modulate RORγt, which is exclusively expressed in Th17 cells and innate lymphoid cells that produce IL-17A, IL-17F, and IL-22. This specific parameter change enables targeted therapy that addresses the root cause of autoimmune pathology while maintaining safety.
Solution Approach 2:
The patent introduces RORγt as an intermediary target between the immune system and disease pathology. By modulating RORγt activity, the compounds control the production of IL-17A, IL-17F, and IL-22, which are the key mediators driving autoimmune inflammation. This intermediary approach allows precise control over the immune response without broad suppression.
2Reliability
If existing ROR modulators are used, then some activity is achieved, but efficacy is insufficient for controlling autoimmune diseases and antibody-mediated rejection
Solution Approach 1:
The patent optimizes the pharmacological parameters of RORγt modulation through a series of compounds with different binding affinities and functional selectivities. The compounds are designed to achieve optimal modulation of RORγt activity, balancing inhibition of pathogenic Th17 cell differentiation with preservation of beneficial immune functions. This parameter optimization results in enhanced therapeutic efficacy.
Solution Approach 2:
The patent applies local quality by designing compounds that specifically target RORγt expressed in Th17 cells and innate lymphoid cells, while leaving other immune cell types unaffected. This selective local modulation at the RORγt receptor level enables precise control over IL-17 producing cell populations without broad immune suppression.
3Object-generated harmful factors
If RORγt activity is inhibited to control autoimmune diseases, then inflammation is reduced, but understanding of molecular pathways is still incomplete
Solution Approach 1:
The patent employs feedback mechanisms by monitoring the effects of RORγt modulation on IL-17A, IL-17F, and IL-22 production. The compounds are designed to provide feedback control over the Th17 cell differentiation pathway, allowing adjustment of modulation intensity to achieve optimal reduction of inflammatory cytokines while maintaining safety and understanding of pathway dynamics.
Data Source
AI summary
The invention encompasses the novel class of compounds represented by the Formula (I), (II), (III) and (IV) below, which are modulators of RORγt:The invention also encompasses pharmaceutical compositions which include the compounds shown above and methods of treating or preventing autoimmune diseases and antibody mediated rejection in a patient in need thereof.