2-Polycyclic Propynyl Adenosine Analogs for Selective A2A Agonism
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Solution Overview
Problem
There is a continuing need for selective A2 adenosine receptor agonists that have reduced side effects, are chemically stable, and short-acting, suitable for therapeutic applications, including inflammatory disease treatment and pharmacological stress imaging, while minimizing adverse effects.
Innovation Solution
Development of novel 2-alkynyladenosine derivatives with specific polycyclic moieties at the ethyn-2-yl position and modified 5′-riboside residues, such as N-(cycloalkyl)carboxyamino or 5- or 6-membered heterocyclic rings, which act as A2A adenosine receptor agonists, potentially used in combination with Type IV phosphodiesterase inhibitors to inhibit inflammatory responses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective adenosine agonists are used to treat inflammatory diseases, then anti-inflammatory effect is achieved, but side effects increase due to activation of multiple receptor subtypes
Solution Approach 1:
The patent applies local quality by introducing specific substituents at defined positions on the adenosine molecule (position 2 with alkynyl groups, position 6 with aromatic substituents, and modifications at the 5'-ribose position) to create compounds that selectively activate A2A receptors while avoiding activation of other adenosine receptor subtypes. This localized modification approach enables the compound to have different binding affinities for different receptor subtypes, achieving selective anti-inflammatory action with reduced side effects.
2Duration of action of moving object
If long-acting adenosine agonists are used to maintain therapeutic effect, then duration of action increases, but chemical stability increases leading to prolonged exposure and potential toxicity
Solution Approach 1:
The patent applies parameter changes by carefully selecting and optimizing the chemical parameters of the adenosine derivatives, specifically the type of substituent at position 2 (alkynyl with specific R groups), the aromatic substituent at position 6, and the 5'-ribose modification. These parameter changes allow tuning of the compound's metabolic stability and receptor binding kinetics to achieve short-acting properties with reduced toxicity, rather than simply increasing duration of action.
3Object-affected harmful factors
If selective A2A adenosine receptor agonists with optimized properties are developed, then side effects are reduced, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the adenosine molecule into distinct functional segments: the core adenosine structure, the position 2 alkynyl substituent with specific R groups, the position 6 aromatic substituent, and the 5'-ribose modification. Each segment contributes specifically to selectivity and pharmacological properties. This modular segmentation allows systematic optimization of each segment to achieve reduced side effects while maintaining manageable overall compound complexity.
Data Source
AI summary
The invention provides compounds having the following general formula (I):wherein X, R1, R2, R7 and Z are as described herein.