Substituted pyrrolidine amines and amides as mediator of the glucocortoid receptor
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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 novel compounds that effectively modulate the glucocorticoid receptor with fewer side effects.
Innovation Solution
Development of novel compounds according to general formula (I) that act as potent modulators of the glucocorticoid receptor, potentially reducing adverse effects by selectively modulating GR-dependent pathways, thereby providing therapeutic benefits for inflammatory disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If chronic glucocorticoid treatment is used to treat inflammatory diseases, then therapeutic efficacy is improved, but adverse effects worsen
Solution Approach 1:
The patent segments the glucocorticoid receptor's functional pathways into transactivation and transrepression mechanisms. The compounds selectively modulate these pathways, enhancing anti-inflammatory transrepression while minimizing side effect-causing transactivation, thereby resolving the contradiction between efficacy and adverse effects
Solution Approach 2:
The compounds exhibit local quality by demonstrating pathway-selective modulation at the molecular level. They preferentially activate beneficial GR-dependent pathways (transrepression of inflammatory genes) while sparing harmful pathways (transactivation of genes causing adverse effects), achieving differentiated therapeutic action
2Duration of action of moving object
If glucocorticoid treatment is discontinued abruptly, then treatment duration is reduced, but withdrawal symptoms worsen
Solution Approach 1:
The compounds enable shorter treatment durations by providing more effective anti-inflammatory action at lower doses or for shorter periods. The enhanced potency and selectivity allow the therapeutic effect to be achieved faster and maintained more efficiently, reducing the need for long-term treatment and associated withdrawal risks
3Object-generated harmful factors
If partial agonists or selective glucocorticoid receptor modulators are developed, then adverse effects are reduced, but clinical approval status worsens (none approved yet)
Solution Approach 1:
The patent applies parameter changes by optimizing the chemical structure (formula I) to achieve improved binding affinity and selectivity parameters. The compounds demonstrate enhanced potency and favorable pharmacokinetic properties that address previous failures of selective modulators, providing the necessary improvements for clinical viability
Data Source
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.