Pyrazolo-pyrrolo-pyrimidine-dione derivatives for selective P2X3 inhibition
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Solution Overview
Problem
Current treatments for neurogenic disorders associated with the P2X3 receptor lack specificity, leading to side effects such as altered taste perception due to non-selective blockade of P2X2/3 receptors, which affects patient compliance and quality of life.
Innovation Solution
Development of novel Pyrazolo-pyrrolo-pyrimidine-dione derivatives that selectively target the P2X3 receptor, reducing the risk of taste disturbances by differentiating between P2X3 and P2X2/3 receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective P2X3 and P2X2/3 receptor antagonists are used, then anti-nociceptive efficacy is improved, but taste perception is altered leading to reduced patient compliance
Solution Approach 1:
The patent segments the P2X receptor blockade into selective P2X3 homomeric receptor antagonism, separating this function from P2X2/3 heteromeric receptor blockade. This segmentation allows achieving anti-nociceptive efficacy through P2X3 selective inhibition while avoiding taste disturbances caused by non-selective P2X2/3 blockade, thus resolving the technical contradiction between efficacy and side effects
Solution Approach 2:
The invention applies local quality by creating compounds with selective affinity for P2X3 homomeric receptors versus P2X2/3 heteromeric receptors. The selective P2X3 antagonists exhibit different binding characteristics and pharmacological properties at the specific P2X3 homomeric receptor site, enabling targeted inhibition that spares taste perception while maintaining pain relief efficacy
2Object-affected harmful factors
If selective P2X3 homomeric receptor antagonists are used, then taste perception is maintained, but anti-nociceptive efficacy may be reduced compared to non-selective antagonists
Solution Approach 1:
The patent employs parameter changes by optimizing the chemical structure of pyrazolo-pyrrolo-pyrimidine-dione derivatives to achieve selective P2X3 homomeric receptor binding with high affinity. By modifying molecular parameters such as substituent groups (R1, R2, R3, R4, R5) and their configurations, the compounds achieve selective P2X3 antagonism with sufficient potency to maintain anti-nociceptive efficacy while preserving taste perception
Data Source
AI summary
The present invention covers substituted. Pyrazolo-pyrrolo-pyrimidine-dione (PPPD) compounds of general formula (I): in which R1, R2 and R3 are as defined herein, methods of preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of neurogenic diseases, as a sole agent or in combination with other active ingredients.