Non-steroidal Glucocorticoid Receptor Modulators for Inflammatory Disease
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current treatments for inflammatory and immune-related diseases, such as rheumatoid arthritis and asthma, face limitations due to the side effects of systemic glucocorticoid use, and there is a need for compounds that can modulate glucocorticoid receptor, AP-1, and NF-κB activity to address both inflammatory and metabolic disorders without inducing unwanted metabolic changes.
Innovation Solution
Development of new non-steroidal compounds with a specific structural formula that modulate glucocorticoid receptor, AP-1, and NF-κB activity, allowing for targeted treatment of inflammatory and immune-related diseases while minimizing metabolic side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If systemic glucocorticoids are used to treat inflammatory diseases, then anti-inflammatory efficacy is improved, but metabolic side effects worsen
Solution Approach 1:
The patent applies local quality by developing compounds that selectively modulate glucocorticoid receptor function to achieve anti-inflammatory effects in specific tissues (such as joints or lungs) while avoiding systemic metabolic disturbances. The compounds provide targeted transrepression of NF-κB and AP-1 in inflammatory sites without the broad metabolic impacts of traditional systemic glucocorticoids.
Solution Approach 2:
The patent utilizes parameter changes by modifying the chemical structure of glucocorticoid receptor modulators to alter their binding affinity and functional selectivity. The compounds of formula (I) incorporate specific structural modifications that change the receptor interaction parameters to achieve anti-inflammatory efficacy while minimizing metabolic side effects through optimized pharmacological properties.
2Reliability
If traditional glucocorticoid therapy is used, then inflammatory disease treatment is effective, but quality of life deteriorates due to side effects
Solution Approach 1:
The patent converts the harmful metabolic side effects of traditional glucocorticoids into a benefit by developing selective modulators that maintain the beneficial anti-inflammatory transrepression function while eliminating the harmful transactivation effects. The compounds selectively inhibit NF-κB and AP-1 without inducing the metabolic disturbances associated with conventional glucocorticoid therapy.
Solution Approach 2:
The patent introduces intermediary compounds that act as selective modulators between the glucocorticoid receptor and its downstream targets. These intermediaries (compounds of formula (I)) facilitate beneficial transrepression of inflammatory pathways while blocking harmful transactivation of metabolic genes, serving as a mediating layer that separates beneficial from harmful effects.
3Object-affected harmful factors
If non-steroidal compounds are developed to replace glucocorticoids, then metabolic side effects are reduced, but development complexity increases
Solution Approach 1:
The patent achieves universality by designing a unified structural framework (formula (I)) that encompasses multiple compounds with similar core structures but varying substituents. This multi-functional scaffold can modulate glucocorticoid receptor activity across different disease indications while maintaining consistent pharmacological properties, reducing the need to develop entirely new compounds for each application.
Solution Approach 2:
The patent applies segmentation by dividing the molecular structure into a core scaffold (the tricyclic system with specific ring arrangements) and variable substituent groups (R1-R11, Z, Q, J1-J3). This modular approach allows systematic variation of functional groups to optimize activity for different diseases while maintaining the core anti-inflammatory mechanism, simplifying the development process compared to creating completely new molecular architectures.
Data Source
AI summary
Novel 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 inflammatory and immune diseases, having the structure of formula (I):an enantiomer, diastereomer, or tautomer thereof, or a prodrug ester thereof, or a pharmaceutically-acceptable salt thereof, in which:Z is heterocyclo or heteroaryl;A is a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring;B is a cycloalkyl, cycloalkenyl, aryl, heterocyclo, or heteroaryl ring, wherein each ring is fused to the A ring on adjacent atoms and optionally substituted by one to four groups which are the same or different and are independently selected from R5, R6, R7, and R8;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, C1-3alkylene, substituted C1-3alkylene, C2-4alkenylene, and substituted C2-4alkenylene, 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.Also provided are pharmaceutical compositions and methods of treating inflammatory- or immune-associated diseases and obesity and diabetes employing said compounds.