Indazolyl Derivatives Glucocorticoid Receptor Modulation
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Solution Overview
Problem
Current non-steroidal glucocorticoid receptor modulators have limitations in selectivity, efficacy, crystallinity, and distribution volume, which affect their anti-inflammatory efficacy and metabolic actions compared to steroidal compounds.
Innovation Solution
Development of novel indazolyl derivatives with specific structural modifications, such as fluoroalkyl groups and phenyl substitutions, to enhance binding affinity, crystallinity, and systemic exposure, acting as modulators of the glucocorticoid receptor with improved properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Object-generated harmful factors
If non-steroidal glucocorticoid receptor modulators are used, then metabolic actions are reduced, but selectivity and efficacy are insufficient
Solution Approach 1:
The patent modifies molecular parameters of the glucocorticoid receptor modulators by introducing specific substituents (fluoroalkyl groups at positions 1 or 7, phenylsulfonyl groups) to optimize the balance between metabolic activity and anti-inflammatory efficacy. These parameter changes in molecular structure achieve reduced metabolic actions while maintaining or improving selectivity and efficacy.
Solution Approach 2:
The patent applies local quality modifications by specifically substituting certain positions on the indazole core structure with particular groups (fluoroalkyl at C1 or C7, phenylsulfonyl at C3 or C5). These localized structural modifications target specific properties to achieve the desired dissociation between metabolic and anti-inflammatory effects.
2Reliability
If known non-steroidal compounds are used, then anti-inflammatory effects are achieved, but crystallinity and distribution volume are insufficient
Solution Approach 1:
The patent changes physical-chemical parameters of the compounds, specifically LogD (distribution coefficient) and crystallinity, through systematic modification of the molecular structure. The introduction of fluorinated alkyl groups and phenylsulfonyl groups optimizes these parameters to achieve improved distribution volume and crystallinity while maintaining anti-inflammatory efficacy.
3Reliability
If known non-steroidal compounds are used, then anti-inflammatory activity is observed, but binding affinity and crystallinity are insufficient
Solution Approach 1:
The patent optimizes binding affinity by changing molecular parameters including the introduction of fluorinated groups (which enhance lipophilicity and receptor interaction) and phenylsulfonyl groups (which provide strong hydrogen bonding capabilities). These parameter changes improve binding affinity to the glucocorticoid receptor while maintaining anti-inflammatory activity.
Data Source
AI summary
A compound of formula la: (Ia) The present invention relates to novel indazolyl derivatives, to pharmaceutical compositions comprising such derivatives, to processes for preparing such novel derivatives and to the use of such derivatives as medicaments.