AHR Agonist Compounds for Immune Suppression Without Dioxin Toxicity
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Solution Overview
Problem
There is a significant unmet need for potent, selective, and safe drugs to treat immune-mediated diseases (IMDs) such as psoriasis, ulcerative colitis, Crohn's disease, graft-versus-host disease, and multiple sclerosis, as current treatments are limited in efficacy.
Innovation Solution
Development of novel AHR agonist compounds, including specific heteroaryl amides and carboxamides, which activate the aryl hydrocarbon receptor (AHR) to regulate immune responses, thereby treating IMDs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If prototypical AHR agonists such as TCDD are used to suppress adaptive immune responses, then immune suppression is achieved, but dioxin-like toxicities occur
Solution Approach 1:
The patent modifies the chemical structure of AHR agonists by changing molecular parameters (substituting chlorine atoms with other groups, modifying the dibenzodioxin core structure) to alter the agonist's binding affinity and signaling properties. This resolves the contradiction by maintaining immune suppression efficacy while reducing dioxin-like toxicities through structural parameter changes that decouple the beneficial immune modulating effects from the harmful toxic effects.
Solution Approach 2:
The patent converts the harmful dioxin-like toxicities associated with prototypical AHR agonists into beneficial effects by developing novel agonists that selectively activate AHR-mediated immune suppression pathways while avoiding the harmful metabolic activation pathways that lead to toxicity. The invention essentially redirects the AHR signaling to produce beneficial immune modulation without the harmful side effects.
2Reliability
If CYP induction is used to detoxify PAHs, then metabolic clearance is improved, but reactive species formation occurs
Solution Approach 1:
The patent employs parameter changes in the AHR agonist molecular structure to modulate CYP enzyme induction patterns. By carefully selecting substituents and structural motifs, the invention achieves selective CYP induction that enhances metabolic clearance of harmful PAHs while controlling the induction level to prevent excessive reactive species formation, thus resolving the contradiction between clearance efficiency and toxicity.
3Reliability
If current treatments for immune-mediated diseases are used, then disease management is achieved, but efficacy is limited
Solution Approach 1:
The patent introduces novel AHR agonist compounds as intermediary substances that mediate immune response modulation. These compounds serve as more effective intermediaries compared to current treatments by directly activating AHR to produce potent immune suppression, thereby enhancing treatment efficacy while managing immune-mediated diseases.
Solution Approach 2:
The patent applies parameter changes in the pharmacological mechanism by transitioning from conventional treatment modalities to AHR-mediated immune modulation. This fundamental parameter change in the treatment approach enables superior efficacy while maintaining disease management capabilities, addressing the limitation of current treatments.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The AHR agonists effectively suppress adaptive immune responses, modulate regulatory T cells and dendritic cells, and upregulate CYP enzymes, providing therapeutic benefits for IMDs like psoriasis, ulcerative colitis, Crohn's disease, and multiple sclerosis.
Implementation Method 1
The present invention provides certain compounds that are agonists of AHR... which activate the aryl hydrocarbon receptor (AHR) to regulate immune responses
Implementation Method 2
AHR also regulates the expression of CYP1A1, CYP1A2 and CYP1B1, which catalyze the metabolism of polycyclic aromatic hydrocarbon (PAH) and other aromatic compounds
Data Source
AI summary
The present invention relates to certain substituted AHR agonist compounds, to pharmaceutical compositions comprising the compounds and to methods of using the compounds to treat immune-mediated diseases.