A2B Adenosine Receptor Antagonist Prodrugs for Solubility
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Solution Overview
Problem
Current A2B adenosine receptor antagonists, such as those with an unsubstituted 7-position xanthine moiety, are insoluble in aqueous media and difficult to formulate using conventional pharmaceutical excipients, leading to unpredictable plasma levels in mammals, which limits their therapeutic effectiveness in treating conditions like asthma and gastrointestinal disorders.
Innovation Solution
Development of prodrug compounds with specific ester or phosphate derivatives at the 7-position of the xanthine moiety, which are more soluble and provide higher plasma levels of the active moiety, allowing for more effective treatment of conditions such as asthma, gastrointestinal disorders, and neurological diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional A2B adenosine receptor antagonists with unsubstituted 7-position xanthine moiety are used, then they can block A2B receptors to treat various diseases, but they are insoluble in aqueous media and difficult to formulate, leading to unpredictable plasma levels
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure at the 7-position of the xanthine moiety, changing it from unsubstituted to substituted with specific ester or phosphate groups. This structural parameter change transforms the compound from insoluble to soluble in aqueous media, enabling proper formulation and predictable plasma levels while maintaining A2B receptor blocking activity
Solution Approach 2:
The patent uses prodrug compounds as intermediaries. The substituted compounds at the 7-position act as prodrugs that are converted in vivo to the active unsubstituted form. This intermediary approach allows the drug to be administered in a soluble, formulable form that then converts to the active therapeutic agent in the body, resolving the contradiction between formulability and therapeutic effectiveness
2Quantity of substance
If prodrug compounds with ester or phosphate derivatives at the 7-position are developed, then solubility and plasma levels improve, but the molecular structure becomes more complex
Solution Approach 1:
The patent systematically explores specific ester and phosphate substitutions at the 7-position, changing molecular parameters to achieve optimal balance between solubility and complexity. By selecting specific substituents (ester or phosphate groups) rather than any arbitrary substitution, the patent achieves improved plasma levels while controlling molecular complexity to manageable levels
Solution Approach 2:
The patent applies local quality by making a specific localized modification only at the 7-position of the xanthine moiety, while leaving the rest of the molecular structure intact. This focused local substitution with ester or phosphate groups improves solubility and plasma levels without requiring comprehensive molecular redesign, thus limiting the increase in overall complexity
Data Source
AI summary
Disclosed are prodrugs of A2B adenosine receptor antagonists, having the following structureand their use in treating mammals for various disease states.