Non-steroidal Glucocorticoid Receptor Modulators for Selective Anti-inflammatory Treatment
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Solution Overview
Problem
Current treatments for inflammatory and immune-related diseases, such as rheumatoid arthritis and obesity, face limitations due to systemic side effects of glucocorticoids and the need for compounds that effectively modulate glucocorticoid receptor (GR), AP-1, and NF-κB activity without adverse effects.
Innovation Solution
Development of new non-steroidal compounds with specific structures that modulate GR, AP-1, and NF-κB activity, as described in the formula (I), which can be used to treat diseases like obesity, diabetes, and inflammatory or immune-associated diseases, while minimizing side effects and improving pharmaceutical properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucocorticoids are used to treat inflammatory diseases, then anti-inflammatory activity is improved, but systemic side effects increase
Solution Approach 1:
The patent segments the glucocorticoid receptor modulation function from the systemic steroid hormone activity by developing non-steroidal compounds that specifically target GR transrepression. This allows selective inhibition of NF-κB and AP-1 transcription factors without activating other steroid hormone receptors, thereby achieving anti-inflammatory effects while avoiding systemic side effects associated with traditional glucocorticoids.
Solution Approach 2:
The invention introduces local quality by designing compounds with specific molecular structures (Formula I) that confer selective affinity for the glucocorticoid receptor's transrepression function. The compounds exhibit differentiated interaction patterns with the GR protein, enabling targeted modulation of inflammatory gene expression while leaving metabolic and other non-inflammatory functions unaffected.
2Reliability
If traditional glucocorticoids are used to modulate GR activity, then anti-inflammatory efficacy is improved, but pharmacological properties deteriorate due to broad receptor interactions
Solution Approach 1:
Instead of using steroidal compounds that naturally interact with multiple hormone receptors, the patent inverts the approach by designing non-steroidal structures that specifically mimic only the transrepression-active conformation of the GR ligand-binding domain. This inverted strategy achieves high selectivity for anti-inflammatory GR modulation while excluding interactions with other steroid hormone receptors.
3Adaptability or versatility
If new non-steroidal compounds are developed to improve selectivity, then pharmaceutical properties are improved, but structural complexity increases
Solution Approach 1:
The patent applies parameter changes by systematically varying key molecular parameters in the compounds of Formula I, including the nature of substituents at positions R1-R23, the saturation state of ring A, and the presence of double bonds. These parameter variations are optimized to achieve the desired balance between GR transrepression selectivity, metabolic stability, and pharmacological properties while maintaining reasonable structural complexity.
Data Source
AI summary
Non-steroidal compounds are provided which are useful in treating diseases associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity including obesity, diabetes, inflammatory and immune diseases, and have the structure of formula (I)or an enantiomer, a diastereomer, a pharmaceutically acceptable salt, or hydrate thereof, where J is selected from NR1 or C(R4)(R4a); K is selected from NR2 or C(R5)(R5a); L is selected from NR3 or C(R6)(R6a); and A, X, Y, R1, R2, R3, R4, R4a, R5, R5a, R6, R6a, R8, R10, R11, and n are defined herein. Also provided are pharmaceutical compositions and methods of treating obesity, diabetes and inflammatory or immune associated diseases comprising said compounds.