Indane Modulators for Glucocorticoid Receptor Selectivity

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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 the side effects of glucocorticoid therapy and the need for compounds that modulate glucocorticoid receptor, AP-1, and NF-κB activity to effectively manage these conditions without systemic side effects.

Innovation Solution

Development of new non-steroidal compounds that modulate glucocorticoid receptor, AP-1, and NF-κB activity, specifically represented by compounds of formula (I), which can be used to treat diseases like obesity, diabetes, and inflammatory or immune-associated diseases by administering a therapeutically effective amount of these compounds.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If glucocorticoid therapy is used to treat inflammatory and immune-related diseases, then anti-inflammatory efficacy is improved, but systemic side effects increase

Engineering Contradiction:

Improveanti-inflammatory efficacyVSAvoidsystemic side effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent segments the glucocorticoid receptor's functions by developing selective modulators that can target specific transcription factors (NF-κB, AP-1) involved in inflammation while avoiding other glucocorticoid-mediated effects that cause side effects. This allows separation of therapeutic benefits from harmful effects.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The invention creates compounds with localized action at the level of specific transcription factor interactions. The modulators are designed to interact specifically with the glucocorticoid receptor's transrepression function on inflammatory genes, providing local precision in molecular targeting rather than systemic glucocorticoid activity.

Inventive Principle:

Principle #3Local quality

2Adaptability or versatility

If new non-steroidal compounds are developed to modulate glucocorticoid receptor activity, then selectivity for inflammatory pathways is improved, but molecular complexity increases

Engineering Contradiction:

Improveselectivity for inflammatory pathwaysVSAvoidmolecular complexity

Core Design Contradiction:

Adaptability or versatilityVSDevice complexity

Solution Approach 1:

The patent employs parameter changes in molecular structure by systematically varying chemical groups and substituents on the core indane scaffold. This allows optimization of selectivity for the glucocorticoid receptor and specific transcription factor interactions while managing molecular complexity through structured chemical variation.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS8324401B2Indane modulators of glucocorticoid receptor, AP-1, and/or NF-κB activity and use thereof

Publication Date: 2012.12.04 BRISTOL MYERS SQUIBB CO

AI summary

Novel non-steroidal compounds are provided that 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 having the structure of formula (I):or enantiomers, diastereomers, or a pharmaceutically-acceptable salt, or hydrate, thereof, where X is A1QA2-; Q is a bond, —C(═O)—, —OC(O)—, —C(═O)NR5—, —SOp—, —SOpNR5—, —C(O)O—, —NR5C(O)—, —OC(O)NR5—, —NR5C(O)O—, —S(O)pNR5C(O)—, —C(O)NR5S(O)p——NR5S(O)p—, or —NR5C(═O)NR6—. Y is selected from hydrogen, C1-6alkyl, OR16, substituted C1-6alkyl, cycloalkyl, aryl, heterocyclo and heteroaryl. A1 and A2 are independently selected from a bond, C1-3alkylene, or C1-3alkenylene, and R1-R11 are defined herein. Also provided are pharmaceutical compositions, combinations, and methods of treating obesity, diabetes and inflammatory- or immune-associated diseases comprising said compounds.