Selective A1 Adenosine Receptor Antagonists for GFR-Sparing Diuresis
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Solution Overview
Problem
Current treatments for congestive heart failure (CHF) using loop diuretics like furosemide decrease glomerular filtration rate (GFR), which is undesirable in patients with compromised renal function, highlighting the need for highly selective A1 adenosine receptor antagonists that can promote sodium excretion without affecting A2a, A2b, and A3 adenosine receptors.
Innovation Solution
Development of pharmaceutical compositions comprising specific A1 adenosine receptor antagonists, such as compounds of Formula I, which are administered to mammals to treat conditions like CHF, chronic renal disease, and cirrhosis, using therapeutically effective doses to selectively target A1 adenosine receptors while sparing GFR.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If loop diuretics like furosemide are used to treat congestive heart failure, then sodium excretion is promoted, but glomerular filtration rate decreases
Solution Approach 1:
The patent changes the molecular parameters of the adenosine receptor antagonist to achieve high selectivity for A1 receptors. By optimizing the purine core structure, N1 substituent, and N6 substituent parameters, the compound achieves selective binding to A1 receptors over other adenosine receptor subtypes, thereby promoting sodium excretion without the harmful effect of decreasing GFR associated with non-selective agents
Solution Approach 2:
The patent divides the adenosine receptor family into different subtypes (A1, A2a, A2b, A3) and targets only the A1 subtype with high selectivity. This segmentation approach allows the drug to activate only the beneficial A1 receptor effects (sodium excretion) while avoiding activation of other subtypes that may have unwanted side effects, thus resolving the contradiction between sodium excretion and GFR preservation
2Productivity
If non-selective adenosine receptor antagonists are used, then diuretic effect is achieved, but side effects from A2a, A2b, and A3 receptor interaction occur
Solution Approach 1:
The patent applies local quality by making the adenosine receptor antagonist selectively active at A1 receptors while being inactive at A2a, A2b, and A3 receptors. The molecular structure is designed with specific properties (purine core, N1 and N6 substituents) that confer selective binding affinity to A1 receptors, thereby achieving diuretic effect locally at the A1 receptor without producing harmful side effects from activation of other receptor subtypes
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The A1 adenosine receptor antagonists effectively promote sodium excretion and increase GFR, providing a treatment for CHF and other conditions without the undesirable side effects associated with interacting with A2a, A2b, and A3 adenosine receptors, thus offering a GFR-sparing diuretic effect.
Implementation Method 1
A1 adenosine receptor antagonists... highly selective A1 adenosine receptor antagonists... blockade of the A1 adenosine receptor
Implementation Method 2
blockade of the A1 adenosine receptor decreases afferent arteriole pressure, leading to an increase in GFR and urine flow, and sodium excretion
Implementation Method 3
blockade of the A1 adenosine receptor decreases afferent arteriole pressure, leading to an increase in GFR
Data Source
AI summary
Disclosed are A1 adenosine receptor antagonists having the general formulaThe compounds are useful for treating various disease states, in particular disease states for which diuretic treatment is appropriate.