Non-steroidal Glucocorticoid Receptor Modulators for Inflammatory Disease
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Solution Overview
Problem
Current treatments for inflammatory and immune-related diseases, such as rheumatoid arthritis and asthma, often rely on glucocorticoids, which have significant side effects due to their systemic use, and there is a need for compounds that can modulate glucocorticoid receptor, AP-1, and NF-κB activity to minimize these side effects while maintaining anti-inflammatory efficacy.
Innovation Solution
Development of new non-steroidal compounds that effectively modulate the glucocorticoid receptor, AP-1, and NF-κB activity, specifically designed to treat inflammatory and immune-associated diseases, with structures that include heterocyclic or heteroaryl side chains attached to a benzo ring, capable of inhibiting or inducing transcriptional activities as needed.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucocorticoids are used to treat inflammatory and immune-related diseases, then anti-inflammatory efficacy is improved, but side effects increase
Solution Approach 1:
The invention segments the glucocorticoid receptor's functions by developing selective modulators that can target specific transcription factors (NF-κB, AP-1) independently. This allows separation of the desired anti-inflammatory effect from the unwanted metabolic side effects, as different tissue responses are mediated through different transcriptional pathways
Solution Approach 2:
The compounds exhibit local quality by demonstrating tissue-selective or cell-type selective modulation of transcription factors. This enables the drug to produce anti-inflammatory effects in immune cells while minimizing metabolic effects in other tissues, achieving spatially differentiated therapeutic action
2Reliability
If traditional glucocorticoid therapy is used, then inflammatory disease symptoms are controlled, but metabolic disorders occur
Solution Approach 1:
The invention extracts the specific anti-inflammatory transcriptional repression function from the complete glucocorticoid receptor action profile. By designing selective modulators that specifically inhibit NF-κB and AP-1 while preserving other glucocorticoid-mediated functions, the harmful metabolic effects are removed while retaining therapeutic benefit
Solution Approach 2:
The invention changes the selectivity parameter of glucocorticoid receptor modulation. Instead of broad-spectrum glucocorticoid activity, the compounds are designed to selectively modulate specific transcription factors (NF-κB, AP-1, STAT3) with defined dissociation constants, altering the action profile from non-selective to highly selective
Data Source
AI summary
Novel non-steroidal compounds are provided which are useful in treating diseases associated with modulation of the glucocorticoid receptor, and/or AP-1 and/or NF-κB activity including inflammatory and immune diseases, obesity and diabetes having the structure of formula (I):, its enantiomers, diastereomers, or a pharmaceutically-acceptable salt, or hydrate, thereof, wherein the group X is O or (Rx)(Ry); is heterocyclo or heteroaryl; E is —N—, —NR1—, —O—, —C(═O), —S—, —SO2—, or —CR2—; F is —N—, —NR1a, —O—, —C(═O), —S—, —SO2—, or —CR2a—; G is independently N, —NR1b—, —O—, —C(═O), —S—, —SO2— or —CR2b— provided that the heterocyclic ring formed does not contain a S—S or S—O bond and at least one of E, F and G is a hetero atom; and Ma, Rx, Ry, R1, R1a, R1b, R2, R2a, R2b, R4, R5a, R6, R7, X, Za and Z are as defined herein. Also provided are pharmaceutical compositions and methods of treating inflammatory- or immune-associated diseases employing said compounds.