Non-steroidal Glucocorticoid Receptor Modulators for Inflammatory Disease
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Solution Overview
Problem
Current treatments for inflammatory and immune-related diseases using glucocorticoids are limited by significant side effects, and there is a need for compounds that can modulate glucocorticoid receptor (GR) activity to address both inflammatory suppression and metabolic disorders without the adverse effects of transactivation.
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 diseases while minimizing side effects by selectively inhibiting or promoting GR activity as needed.
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 worsen
Solution Approach 1:
The patent segments the glucocorticoid receptor's functions into two distinct pathways: transrepression (anti-inflammatory effect) and transactivation (metabolic side effects). By developing selective modulators that can preferentially inhibit transrepression or transactivation, the invention separates these previously coupled functions, allowing treatment of inflammatory diseases while minimizing metabolic side effects.
Solution Approach 2:
The patent applies local quality by creating compounds with different molecular structures that selectively interact with specific regions or conformations of the glucocorticoid receptor. This enables the receptor to exhibit different functional qualities (anti-inflammatory vs. metabolic effects) in different cellular contexts, achieving tissue-selective or pathway-selective modulation.
2Object-affected harmful factors
If glucocorticoid receptor transactivation is inhibited, then metabolic side effects are reduced, but anti-inflammatory efficacy may be compromised
Solution Approach 1:
The patent employs dynamic modulation by developing reversible, non-steroidal compounds that can be finely tuned in their binding characteristics. These compounds dynamically interact with the glucocorticoid receptor, allowing for adjustable selectivity between transrepression and transactivation pathways based on molecular design, thereby optimizing the therapeutic window.
Solution Approach 2:
The patent utilizes parameter changes by modifying molecular parameters of the compounds (such as steric bulk, electronic properties, and binding affinity) to achieve selective modulation of GR functions. By adjusting these parameters, the compounds can preferentially inhibit transactivation while preserving transrepression, or vice versa, depending on the desired therapeutic outcome.
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, obesity and diabetes having the structure of formula (I) an enantiomer, diastereomer, tautomer, solvate (e.g. a hydrate), or a pharmaceutically-acceptable salt, thereof, wherein: M is selected from alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, and heteroaryl, provided that if M is alkyl then R6 and R7 taken together with the carbon atom to which they are both attached are selected from a group other than cycloalkyl; Q is selected from (i) hydrogen, C1-C4 alkyl, and substituted C1-C4 alkyl; or (ii) Q and R6 are combined with the carbon atoms to which they are attached to form a 3- to 6-membered cycloalkyl; or (iii) Q and MaM are combined with the carbon atom(s) to which they are attached to form a 3- to 7-membered ring containing 1-2 heteroatoms which are independently selected from the group consisting of O, S, SO2, and N which ring may be optionally substituted with 0-2 R5 groups or carbonyl; Z is selected from cycloalkyl, heterocyclo, aryl, or heteroaryl; and Ma, Za, R1, R2, R3, R4, R6, R7, and R22 are as defined herein. Also provided are pharmaceutical compositions and methods of treating metabolic and inflammatory- or immune-associated diseases or disorders using said compounds.