Bicyclic Pyrazole Compounds Targeting RORgammaT

Solution Overview

Problem

Current therapies for immune and inflammatory disorders, such as psoriasis and rheumatoid arthritis, often have detrimental side effects or lead to patient resistance, highlighting a need for improved treatments that effectively target RORgammaT-mediated diseases.

Innovation Solution

Development of compounds that alter the interaction of coregulator proteins with RORgammaT to antagonize its transcriptional activity, thereby treating autoimmune and inflammatory diseases by inhibiting RORgammaT-mediated conditions.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current therapies for immune and inflammatory disorders are used, then disease treatment is achieved, but detrimental side effects occur and patient resistance develops

Engineering Contradiction:

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing compounds that specifically target RORgammaT in Th17 cells and related lymphoid cells, rather than using broad-spectrum immunosuppressants. The compounds (Formula I, II, III) are structurally optimized to interact with RORgammaT's ligand-binding domain, providing selective inhibition in the specific cellular context of autoimmune and inflammatory diseases, thereby reducing off-target effects and resistance.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by modifying the chemical structure of RORgammaT ligands through systematic variation of molecular parameters (Formula I-III). These structural modifications optimize binding affinity and selectivity for RORgammaT, enabling effective inhibition with reduced side effects. The compounds represent a series of molecules with adjusted chemical parameters to achieve the desired therapeutic profile.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If broad-spectrum immunosuppressants are used to treat autoimmune diseases, then disease activity is reduced, but overall immune function is compromised

Engineering Contradiction:

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent applies segmentation by dividing the immune system into specific functional compartments and targeting only the problematic Th17 cell subset. Instead of suppressing all immune cells, the compounds selectively inhibit RORgammaT signaling in Th17 cells and related lymphoid cells (ILC3s, NK T cells), leaving other immune functions intact. This segmented approach maintains overall immune health while controlling autoimmune pathology.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent inverts the conventional approach by not suppressing immune function broadly, but rather by selectively enhancing or maintaining specific protective functions (Th17 cell-mediated immunity against extracellular bacteria and fungi) while inhibiting the harmful aspect (autoimmunity). This inversion allows disease control without compromising overall immune health.

Inventive Principle:

Principle #13The other way round (Inversion)

Data Source

PatentEP3368516B1SUBSTITUTED BICYCLIC PYRAZOLE COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF

Publication Date: 2020.07.15

AI summary

The present invention relates to compounds according to Formula I: and pharmaceutically acceptable salts thereof. Such compounds can be used in the treatment of RORgammaT-mediated diseases or conditions.