M2 Receptor Allosteric Modulators for Heart Failure
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Solution Overview
Problem
Current treatments for cardiovascular diseases and kidney diseases lack effective and safe drug therapies, particularly for patients with reduced left ventricular pump function and severe heart failure, where existing options like beta blockers and calcium antagonists are inadequate, and there is a need for new therapies that can selectively modulate the muscarinic M2 receptor without causing significant side effects.
Innovation Solution
Development of new 7-substituted 1-aryl-naphthyridine-3-carboxamides as positive allosteric modulators of the muscarinic M2 receptor, which exhibit subtype selectivity and higher affinity for the M2 receptor compared to other muscarinic receptors, thereby enhancing the effects of acetylcholine and reducing the risk of receptor overactivation and side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If beta blockers and calcium antagonists are used for treating cardiovascular diseases, then some therapeutic effect is achieved, but they are inadequate for patients with reduced left ventricular pump function and severe heart failure, and cause significant side effects
Solution Approach 1:
The patent changes the pharmacological parameter from traditional beta-blockade or calcium channel blockade to positive allosteric modulation of muscarinic M2 receptors. This parameter change enables enhanced parasympathetic activity which improves cardiac function in heart failure patients without the harmful side effects of conventional therapies, addressing both therapeutic effectiveness and safety requirements
Solution Approach 2:
The patent introduces a new class of compounds (7-substituted 1-aryl-naphthyridine-3-carboxamides) as intermediary substances that act as positive allosteric modulators. These compounds bind to allosteric sites on M2 receptors and enhance the effect of endogenous acetylcholine, providing a novel therapeutic mechanism that avoids the side effects of beta blockers and calcium antagonists while treating cardiovascular diseases
2Reliability
If orthosteric agonists are used to activate M2 receptor, then receptor activation is achieved, but selectivity towards different muscarinic subtypes is poor and receptor overactivation occurs
Solution Approach 1:
The patent uses allosteric modulators as intermediary substances that indirectly enhance M2 receptor activation through endogenous acetylcholine rather than directly activating the orthosteric site. This intermediary mechanism provides subtype selectivity and prevents overactivation, as the effect is self-limiting and dependent on endogenous ligand presence
Solution Approach 2:
The patent targets a specific allosteric binding site on the M2 receptor that is spatially distinct from the orthosteric site. This local targeting provides subtype selectivity because the allosteric site structure differs among muscarinic subtypes, allowing selective modulation of M2 receptors without affecting other subtypes
3Reliability
If positive allosteric modulators are used to enhance acetylcholine effects, then therapeutic benefits are achieved, but the compounds must demonstrate high subtype selectivity to avoid side effects
Solution Approach 1:
The patent achieves subtype selectivity by targeting a specific allosteric site on M2 receptors that has distinct structural characteristics compared to other muscarinic subtypes. The 7-substituted 1-aryl-naphthyridine-3-carboxamide compounds are designed to interact with this specific local structure, providing high M2 selectivity and minimizing off-target effects
Solution Approach 2:
The patent optimizes the selectivity parameter by modifying the chemical structure of the naphthyridine core and its substituents. Specific substitutions at the 7-position and aryl group modifications tune the compound's affinity and selectivity for M2 receptors, achieving the required precision for selective modulation without side effects
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
These compounds demonstrate potent and selective allosteric modulation of the M2 receptor, offering a new therapeutic approach for cardiovascular and kidney diseases by enhancing parasympathetic activity, reducing inflammation, and improving mitochondrial function, with a favorable safety profile and reduced risk of side effects.
Implementation Method 1
The M2R has an orthosteric as well as an allosteric binding site. The binding of the alloster results in a modulation of the binding affinity and/or effectiveness of the orthosteric agonist.
Implementation Method 2
The activation of the M2 receptor by the endogenous agonist acetylcholine occurs through the binding of the agonist to the so-called orthosteric binding site of the receptor and a resulting change in the conformation of the receptor or stabilization of the active receptor conformation.
Implementation Method 3
M2R stimulation by the agonist acetylcholine causes an inhibition of adenyl cyclase and an activation of the inwardly rectifying potassium channel (IKACh channel, GIRK: G protein activated inwardly rectifying K+ channel; also Kir3.x). This increases the potassium conductivity
Implementation Method 4
This increases the potassium conductivity, which leads to hyperpolarization of the muscle cells. Accordingly, the cells become more difficult to depolarize
Data Source
AI summary
The present application relates to positive allosteric modulators of the muscarinic M2 receptor, in particular novel 7-substituted 1-aryl-naphthyridin-3-carboxylic acid amides, to processes for the preparation thereof, to the use thereof alone or in combinations for the treatment and/or prevention of diseases, and to the use thereof for the production of medicaments for the treatment and/or prevention of diseases, particular for the treatment and/or prevention of cardiovascular disorders and/or renal diseases.