A2B Adenosine Receptor Prodrugs for Stable Plasma Bioavailability
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Solution Overview
Problem
A2B adenosine receptor antagonists are insoluble in aqueous media and difficult to formulate using conventional pharmaceutical excipients, leading to inconsistent plasma levels in mammals, particularly humans.
Innovation Solution
Development of new prodrugs of A2B adenosine receptor antagonists to improve formulation, pharmacokinetic profile, and bioavailability, including compounds like 8-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-3-ethyl-1-propyl-1H-purine-2,6(3H,7H)-dione, which are designed to be stable in acidic environments and resistant to esterase hydrolysis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of manufacture
If conventional pharmaceutical excipients are used to formulate A2B adenosine receptor antagonists, then formulation is simplified, but plasma levels become inconsistent and bioavailability decreases
Solution Approach 1:
The patent modifies the chemical structure of A2B adenosine receptor antagonists by introducing fluorinated alkyl groups and other substituents at specific positions (R1-R5) to alter solubility parameters. This enables the compounds to achieve consistent plasma levels while maintaining pharmacological activity, resolving the contradiction between formulation ease and plasma level consistency.
Solution Approach 2:
The patent creates composite molecular structures combining the core purine scaffold with various substituted groups (fluorinated alkyl, aryl, heteroaryl, etc.). These composite structures improve both solubility and pharmacokinetic properties, allowing consistent plasma levels to be achieved without sacrificing formulation simplicity.
2Reliability
If A2B adenosine receptor antagonists are administered to improve therapeutic effects, then bioavailability is enhanced, but formulation difficulty increases due to insolubility
Solution Approach 1:
The patent systematically varies substituent parameters (fluorinated alkyl chains, aromatic rings, heterocyclic groups) to optimize the balance between solubility and bioavailability. By changing these molecular parameters, the compounds achieve improved bioavailability while remaining formulable with conventional excipients.
Solution Approach 2:
The patent introduces specific functional groups at localized positions (R1-R5) on the purine scaffold to improve solubility without affecting the core pharmacophore. This local modification approach enhances bioavailability while maintaining the ability to use standard formulation techniques.
3Reliability
If new prodrugs are developed to improve solubility and bioavailability, then plasma level consistency improves, but molecular complexity increases
Solution Approach 1:
The patent employs systematic parameter changes at defined positions on the purine scaffold to achieve plasma level consistency. By limiting modifications to specific R-groups rather than the core structure, molecular complexity is controlled while still achieving the desired pharmacokinetic improvements.
Solution Approach 2:
The patent creates a series of compounds with a universal purine scaffold that can accommodate various substituents. This multi-functional approach allows a single core structure to serve multiple purposes (maintaining activity, improving solubility, enabling consistent plasma levels) without proportionally increasing complexity.
Data Source
AI summary
The present disclosure relates generally to adenosine receptor modulator compounds of formula (I), and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of A2B adenosine receptor activity.