AhR Agonist Derivatives With Better Topical Solubility
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Solution Overview
Problem
Existing aryl hydrocarbon receptor (AhR) agonists face limitations due to toxicology and pharmacokinetic issues, particularly with oral dosage forms leading to systemic exposure and adverse events, while topical forms have better tolerability but limited bioavailability due to poor solubility and dissolution of compounds like indirubin.
Innovation Solution
Development of compounds with improved dissolution and solubility, including stereoisomers, pharmaceutically acceptable salts, and tautomers of AhR agonists, formulated in pharmaceutical compositions for targeted delivery to treat inflammatory and immune disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If oral dosage forms of AhR agonists are used, then systemic exposure is achieved, but toxicology issues and adverse events occur
Solution Approach 1:
The patent uses the skin as an intermediary barrier to prevent systemic exposure. Topical application delivers AhR agonists locally to skin conditions while the skin barrier prevents compound entry into the bloodstream, thus achieving therapeutic effect without systemic toxicity
Solution Approach 2:
The invention applies AhR agonists locally to affected skin areas rather than systemically. This localized delivery ensures high concentration at the target site for treating skin conditions while minimizing exposure to other body systems, reducing adverse events
2Object-affected harmful factors
If topical dosage forms are used, then tolerability is improved, but bioavailability is limited due to poor solubility and dissolution
Solution Approach 1:
The patent modifies physical parameters of AhR agonists by creating derivatives with improved solubility and dissolution properties. These structural modifications maintain AhR agonist activity while enhancing solubility, thereby improving bioavailability for topical delivery
Solution Approach 2:
The invention develops composite pharmaceutical formulations combining AhR agonist derivatives with excipients and delivery systems. These composite materials enhance solubility and dissolution rate, improving bioavailability while maintaining the benefits of topical administration
3Reliability
If indirubin is used, then AhR agonist activity is achieved, but dissolution and solubility are poor due to crystalline structure and hydrogen bonding
Solution Approach 1:
The patent systematically modifies the chemical structure of indirubin by introducing substitutions and derivatives. These structural changes disrupt the highly crystalline structure and reduce intra/intermolecular hydrogen bonding, thereby improving dissolution and solubility while preserving AhR agonist activity
Solution Approach 2:
The invention breaks down the rigid crystalline structure of indirubin through chemical modification. By introducing functional groups and structural variations, the compound is segmented into forms with reduced lattice energy and improved solubility characteristics
Data Source
AI summary
A compound having one of the following structures of Formula (IV) or (V):or a stereoisomer, salt, or tautomer thereof, wherein R1, R2, R3, R4, R5 R6, R7, R8, R10, R11a R11b, R12a R12b, X, Y, and Z are as defined herein. Pharmaceutical composition comprising the compounds, and their use in methods of treating diseases are also described.