TREM-1 Inhibition Using SR1903 While Preserving Thymic Function
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Solution Overview
Problem
There is a need for additional inhibitors of RORγ and methods of use thereof, particularly to target Triggering Receptor Expressed on Myeloid cells 1 (TREM-1) for treating inflammation and autoimmune diseases, as existing compounds like SR2211 have limited therapeutic effects and impact thymic function.
Innovation Solution
The development of SR1903, a compound with a broadened nuclear receptor activity profile, including RORγ inverse agonism, mild PPARγ inverse agonism, and LXR agonism, effectively inhibits TREM-1 and modulates immune responses, preserving thymic function and providing anti-inflammatory and anti-diabetic effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing RORγ inhibitors like SR2211 are used to target TREM-1, then TREM-1 inhibition is achieved, but thymic function is impaired and therapeutic effects are limited
Solution Approach 1:
The patent modifies the chemical structure of existing RORγ inhibitors by changing parameters such as substituting fluorine atoms for chlorine atoms, adding hydroxyl groups, and modifying aromatic ring structures. These parameter changes in the molecular structure of SR1903 relative to SR2211 result in improved therapeutic efficacy through enhanced TREM-1 inhibition while preserving thymic function.
2Reliability
If selective RORγ inhibition is pursued to treat inflammation, then anti-inflammatory effect is achieved, but broader nuclear receptor activity needed for optimal therapy
Solution Approach 1:
SR1903 is designed to interact with multiple nuclear receptors including RORγ, PPARγ, and LXR, providing multi-functional activity. This universality allows the compound to simultaneously achieve anti-inflammatory effects through RORγ inhibition while also modulating metabolic pathways via PPARγ and LXR, thereby treating both inflammatory and metabolic components of disease.
3Productivity
If TREM-1 inhibition is targeted for autoimmune disease treatment, then disease progression is slowed, but compound selectivity and precision needed
Solution Approach 1:
The patent achieves local quality by designing SR1903 with specific molecular features that confer selective affinity for TREM-1 and certain nuclear receptors while sparing other immune pathways. The compound's structure includes specific functional groups and spatial arrangements that enable precise targeting of the desired molecular interactions, thereby achieving high selectivity for TREM-1 inhibition over other immune mediators.
Data Source
AI summary
Disclosed herein are methods and uses of the polypharmacological modulator SR1903 and related compounds for inhibiting triggering receptor expressed on myeloid cells-1 (TREM-1) and treating diseases and conditions that are related to or mediated by TREM-1, such as inflammatory diseases, autoimmune diseases, metabolic disorders, and castration resistant prostate cancer (CRPC).