Glucocorticoid Agonist Conjugates With Lower Side Effects
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Solution Overview
Problem
Existing glucocorticoid receptor agonists used for treating inflammatory disorders suffer from significant side effects and stability issues, limiting their therapeutic potential.
Innovation Solution
Development of novel glucocorticoid receptor agonists with an anilino functionality at position(s) 17/16 for conjugation with a linker, combined with modifications at position-20 for fine-tuning, resulting in high potency, stability, and low immunogenicity, suitable for use alone or in immunoconjugates.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If synthetic glucocorticoid receptor agonists (e.g., dexamethasone, prednisolone, budesonide) are used to treat inflammatory disorders, then anti-inflammatory activity is achieved, but severe side effects occur
Solution Approach 1:
The patent applies local quality by introducing specific substituents at defined positions (R1-R5) of the glucocorticoid core structure. Each substituent position is optimized independently to enhance anti-inflammatory activity while reducing specific side effects. For example, R4 is specifically set to OC(O)—R7 where R7 is an aniline or dioxolane-substituted aniline group, creating a localized modification that improves therapeutic index without compromising overall efficacy.
Solution Approach 2:
The patent systematically varies chemical parameters including substituent types (halogen, alkyl, heterocyclic groups), their positions, and stereochemistry to optimize the therapeutic profile. The core structure features variable parameters at multiple positions that allow fine-tuning of pharmacokinetic and pharmacodynamic properties to reduce side effects while maintaining potency.
2Duration of action of moving object
If glucocorticoid receptor agonists are used for chronic disease treatment, then inflammatory control is achieved, but stability issues and aggregation propensity limit therapeutic potential
Solution Approach 1:
The patent creates composite molecular structures by combining the glucocorticoid core with stable substituent groups such as heterocyclic rings (R5 being NR5aR5b or CH2R5c with specific constraints) and aromatic systems. These composite structures enhance overall molecular stability and reduce aggregation propensity while maintaining biological activity for chronic treatment applications.
3Adaptability or versatility
If glucocorticoid receptor agonists are developed for immunoconjugates, then targeted therapy is enabled, but lack of suitable potent agonists with appropriate properties limits development
Solution Approach 1:
The patent designs glucocorticoid agonists with universal applicability for both standalone therapy and immunoconjugate applications. The core structure with defined substituent patterns (particularly R4 as OC(O)—R7 with aniline or dioxolane-aniline) provides a platform that can be conjugated to antibodies or other targeting moieties while retaining potent glucocorticoid activity, enabling dual use scenarios.
Data Source
AI summary
The invention provides novel glucocorticoid receptor agonists and immunoconjugates thereof, as well as pharmaceutical compositions and methods of preparation and use for treating various diseases and disorders (e.g., inflammatory disorders).