Non-steroidal Glucocorticoid Receptor Modulators for Selective Anti-inflammatory Activity
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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 side effects from systemic glucocorticoid use and the need for compounds that effectively modulate glucocorticoid receptor, AP-1, and NF-κB activity without adverse effects.
Innovation Solution
Development of new non-steroidal compounds that specifically target glucocorticoid receptor, AP-1, and NF-κB activity, providing pharmaceutical compositions and methods for treating obesity, diabetes, and inflammatory or immune-associated diseases by administering therapeutically effective amounts of these compounds.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glucocorticoids are used to treat inflammatory diseases, then anti-inflammatory activity is improved, but side effects increase
Solution Approach 1:
The invention segments the glucocorticoid receptor interaction into two distinct functional components: transrepression (anti-inflammatory activity) and transactivation (side effects). By designing compounds that selectively engage only the transrepression pathway through specific conformational changes in the receptor, the patent achieves anti-inflammatory efficacy while eliminating transactivation-mediated side effects.
Solution Approach 2:
The patent applies local quality by creating compounds with specific molecular structures (non-steroidal frameworks with particular substituent patterns) that induce localized conformational changes in the glucocorticoid receptor. These structural modifications ensure that only specific regions of the receptor are activated, enabling selective transrepression without triggering transactivation.
2Reliability
If systemic glucocorticoids are administered, then inflammatory disease treatment is improved, but peak-to-trough blood concentration increases
Solution Approach 1:
The patent employs periodic action through controlled-release formulations and dosing regimens that maintain steady plasma concentrations of the compounds. By administering drugs at optimized intervals and using formulations that provide sustained release, the invention minimizes peak-to-trough fluctuations while maintaining therapeutic efficacy throughout the dosing period.
3Reliability
If glucocorticoid receptor modulators are used, then NF-κB and AP-1 inhibition is improved, but clinical interactions increase
Solution Approach 1:
The patent uses the glucocorticoid receptor itself as an intermediary to achieve NF-κB and AP-1 inhibition. By designing compounds that bind to the glucocorticoid receptor and induce conformational changes, the invention leverages the receptor's natural protein-protein interaction capabilities to block transcription factor activity, avoiding direct interaction with multiple other targets and thereby reducing clinical interaction liability.
Data Source
AI summary
A class of 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 obesity, diabetes, inflammatory and immune diseases, and have the structure of formula (I) or (II):including a stereoisomer thereof, a tautomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, where Q is selected from N, O, and S; Y is aryl or heteroaryl; Z is H, C2-6alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, or alkoxy; and A, B, R, Ra, Rb, Rc and Rd are defined herein. Also provided are pharmaceutical compositions and methods of treating obesity, diabetes and inflammatory or immune associated diseases comprising said compounds.