Non-steroidal Glucocorticoid Receptor Modulators for Selective Anti-inflammatory Therapy
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for inflammatory and immune diseases using glucocorticoids are limited by significant side effects, and there is a need for compounds that can modulate glucocorticoid receptor, AP-1, and NF-κB activity to treat both inflammatory and metabolic disorders without the adverse effects associated with glucocorticoid therapy.
Innovation Solution
Development of new non-steroidal compounds that effectively modulate the glucocorticoid receptor, AP-1, and/or NF-κB activity, allowing for the treatment of metabolic and inflammatory disorders while minimizing side effects by retaining anti-inflammatory efficacy and potentially addressing transactivation and transrepression mechanisms.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucocorticoids are used to treat inflammatory diseases, then anti-inflammatory efficacy is improved, but side effects increase
Solution Approach 1:
The patent segments the glucocorticoid receptor's functions into transactivation and transrepression pathways. The invention selectively modulates the transrepression pathway (which provides anti-inflammatory effects) while minimizing activation of the transactivation pathway (which causes side effects). This is achieved through non-steroidal compounds that specifically target the GR's interaction with transcription factors like NF-κB and AP-1 without fully activating the receptor's DNA binding activity.
Solution Approach 2:
The invention applies local quality by creating compounds with specific molecular structures (non-steroidal framework with particular substituent patterns) that confer selective affinity for the glucocorticoid receptor's transrepression function. The compounds possess specific structural features (such as the core structure with defined R1-R6 substituents) that enable them to interact preferentially with the GR's transrepression interface rather than its transactivation domain.
2Adaptability or versatility
If traditional glucocorticoid therapies are used, then inflammatory and immune disorders are treated, but metabolic side effects occur
Solution Approach 1:
The invention extracts the beneficial anti-inflammatory and immunosuppressive effects of glucocorticoids from their harmful metabolic side effects. By designing non-steroidal compounds that selectively engage the GR's transrepression pathway, the invention isolates the therapeutic actions (inhibition of NF-κB and AP-1) from the metabolic disruptions caused by full GR activation, thereby treating inflammatory and immune disorders without the characteristic metabolic side effects of traditional glucocorticoids.
Data Source
AI summary
Novel non-steroidal compounds are provided which are useful in treating diseases or disorders associated with modulation of the glucocorticoid receptor, AP-1, and/or NF-κB activity, including metabolic and inflammatory and immune diseases or disorders, having the structure of formula (I): an enantiomer, diastereomer, or taυtomer thereof, or a prodrug ester thereof, or a pharmaceutically-acceptable salt thereof, in which: Z is heterocyclo or heteroaryl; •A is a S- to 8-membered carbocyclic ring or a S- to 8-membered heterocyclic ring; B1 and B2 rings are pyridyl rings, wherein the B1 and B2 rings are each fused to the A ring and the B1 ring is optionally substituted by one to three groups which are the same or different and are independently selected from R1, R2, and R4, and the B2 ring is optionally substituted by one to three groups which are the same or different and are independently selected from R5, R7, and R3 J1, J2, and J3 are at each occurrence the same or different and are independently -A1QA2-; Q is a bond, O, S, S(O), or S(O)2; A1 and A2 are the same or different and are at each occurrence independently selected from a bond, C1-3 alkylene, substituted C1-3 alkylene, C2-4 alkenylene, and substituted C2-4 alkenylene, provided that A1 and A2 are chosen so that ring A is a 5- to 8-membered carbocyclic or heterocyclic ring; R1 to R11 are as defined herein.