Non-steroidal Glucocorticoid Receptor Agonists for Inflammation
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Solution Overview
Problem
Current glucocorticoids used for treating inflammation and allergic conditions are associated with significant side effects due to pathological increases in endogenous cortisol or systemic administration, limiting their efficacy due to adverse effects such as bone mineral density reduction, growth slowing, skin bruising, cataract development, and dysregulation of lipid and glucose metabolism.
Innovation Solution
Development of non-steroidal compounds, specifically those of formula (I), which are glucocorticoid receptor agonists, including enantiomers and atropisomers, that modulate the glucocorticoid receptor to provide therapeutic benefits with potentially reduced side effects, particularly upon topical administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucocorticoids are used to treat inflammation and allergic conditions, then therapeutic efficacy is improved, but side effects such as bone mineral density reduction, growth slowing, skin bruising, cataract development, and metabolic dysregulation worsen
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of glucocorticoids from steroidal to non-steroidal compounds (formula I), altering molecular parameters such as core structure, substituent groups, and stereochemistry to achieve selective GR agonism with reduced side effects
Solution Approach 2:
The patent applies local quality by designing compounds with specific local molecular features - particular substituent patterns at defined positions on the core structure, and specific stereochemical configurations that enable selective interaction with the glucocorticoid receptor to enhance therapeutic efficacy while minimizing systemic side effects
2Reliability
If systemic glucocorticoids are administered to achieve therapeutic effects, then anti-inflammatory activity is improved, but adverse effects on multiple organ systems worsen
Solution Approach 1:
The patent applies parameter changes by transitioning from steroidal to non-steroidal chemical structures (formula I), fundamentally altering pharmacological parameters including receptor selectivity, metabolic stability, and tissue distribution to reduce adverse effects while maintaining anti-inflammatory activity
Solution Approach 2:
The patent applies copying by creating non-steroidal compounds that replicate the therapeutic function of natural glucocorticoids through artificial molecular structures (formula I) that mimic the bioactive conformation and receptor interaction patterns of endogenous ligands
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 compounds effectively bind to the glucocorticoid receptor, offering anti-inflammatory and anti-allergic effects, potentially reducing side effects associated with traditional glucocorticoid use, and are suitable for treating inflammatory and allergic disorders like rheumatoid arthritis, asthma, and skin diseases.
Implementation Method 1
The compounds effectively bind to the glucocorticoid receptor, offering anti-inflammatory and anti-allergic effects
Data Source
AI summary
The present invention provides glucocorticoid receptor agonists of formula (I), a process for their preparation, pharmaceutical compositions comprising the compounds and the preparation of said compositions, intermediates and use of the compounds for the manufacture of a medicament for therapeutic treatment, particularly for the treatment of inflammation, allergy and/or skin disease.