Pyrrolidine Amide GR Modulators With Reduced Glucocorticoid Side Effects

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Solution Overview

Problem

Chronic glucocorticoid (GC) treatment for inflammatory diseases is hindered by severe adverse effects, and existing partial agonists or selective glucocorticoid receptor modulators have not been approved for clinical use, necessitating the development of novel compounds that effectively modulate the glucocorticoid receptor with reduced side effects.

Innovation Solution

Development of novel compounds according to general formula (I) that act as potent modulators of the glucocorticoid receptor, specifically designed to preferentially activate anti-inflammatory pathways while minimizing transactivation, thereby reducing adverse effects.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If glucocorticoids are used to treat inflammatory diseases, then anti-inflammatory effects are achieved, but severe adverse effects occur

Engineering Contradiction:

Improveanti-inflammatory effectVSAvoidadverse effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the glucocorticoid receptor's functional pathways into transactivation and transrepression mechanisms. The compound is designed to selectively modulate these pathways, activating anti-inflammatory transrepression while minimizing pro-inflammatory transactivation, thereby separating therapeutic effects from adverse effects at the molecular mechanism level

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The compound exhibits local quality by demonstrating pathway-selective activity within the glucocorticoid receptor system. It preferentially activates specific genomic pathways (transrepression of inflammatory genes) while avoiding others (transactivation of genes causing adverse effects), creating different functional qualities within the same receptor target

Inventive Principle:

Principle #3Local quality

2Ease of operation

If glucocorticoids are discontinued abruptly, then treatment is simplified, but severe withdrawal symptoms occur

Engineering Contradiction:

Improvetreatment simplicityVSAvoidwithdrawal symptoms

Core Design Contradiction:

Ease of operationVSObject-affected harmful factors

Solution Approach 1:

The compound prepares the adrenal gland for discontinuation by maintaining glucocorticoid receptor activation and preventing adrenal suppression during treatment. This preliminary protective action allows for easier discontinuation without severe withdrawal symptoms, as the adrenal gland remains functional and ready to resume endogenous cortisol production

Inventive Principle:

Principle #10Preliminary action

3Object-affected harmful factors

If existing partial agonists or selective glucocorticoid receptor modulators are developed, then adverse effects are reduced, but clinical approval has not been achieved

Engineering Contradiction:

Improveadverse effectsVSAvoidclinical efficacy

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The compound optimizes key pharmacological parameters including potency (IC50 values), selectivity ratio between transrepression and transactivation, and pharmacokinetic properties. By carefully adjusting these parameters, the compound achieves both reduced adverse effects and maintained clinical efficacy, addressing the shortcomings of previous modulators

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS12540130B2Substituted pyrrolidine amides IV

Publication Date: 2026.02.03 GRUNENTHAL GMBH

AI summary

The invention relates to compounds according to general formula (I),which act as modulators of the glucocorticoid receptor and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.