7-Substituted 1-Arylnaphthyridine-3-Carboxamides for M2 Receptor Modulation

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Solution Overview

Problem

Current treatments for cardiovascular disorders and renal disorders lack effective, potent, and safe options for modulating the muscarinic M2 receptor, particularly in conditions like atrial fibrillation and heart failure, where existing medications have limitations such as side effects and inadequate efficacy.

Innovation Solution

Development of novel 7-substituted 1-arylnaphthyridine-3-carboxamides that act as positive allosteric modulators of the muscarinic M2 receptor, enhancing the receptor's activity with improved specificity and safety profile by modulating the receptor's conformation without direct activation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional orthosteric agonists are used to activate M2 receptors, then receptor activation is achieved, but selectivity among muscarinic receptor subtypes is poor and side effects increase

Engineering Contradiction:

Improvereceptor activation efficacyVSAvoidside effects and lack of subtype selectivity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces allosteric modulators as intermediary compounds that indirectly activate M2 receptors by binding to allosteric sites rather than directly competing at the orthosteric site. This intermediary mechanism allows for selective M2 receptor modulation without the broad, non-selective activation caused by conventional orthosteric agonists, thereby reducing side effects while maintaining therapeutic efficacy.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention employs compounds with specific local structural features (such as the 7-substituted 1-arylnaphthyridine-3-carboxylic acid amide structure) that are designed to interact specifically with the M2 receptor's allosteric site. This local structural optimization enables selective binding and modulation of M2 receptors while minimizing interactions with other muscarinic receptor subtypes, thus improving subtype selectivity and reducing harmful side effects.

Inventive Principle:

Principle #3Local quality

2Reliability

If M2 receptor agonists are used to treat cardiovascular disorders, then therapeutic effect is achieved, but safety profile is compromised due to overactivation and toxic effects

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidtoxic effects from receptor overactivation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent utilizes partial agonist properties of the allosteric modulators, where the compounds provide sufficient M2 receptor activation to achieve therapeutic effects but avoid excessive activation that leads to toxic effects. The allosteric modulation mechanism inherently limits maximal activation compared to full orthosteric agonists, providing a built-in safety mechanism that prevents receptor overactivation while maintaining adequate therapeutic response.

Inventive Principle:

Principle #16Partial or excessive action

Solution Approach 2:

The invention exploits the feedback mechanism inherent in allosteric modulation, where the modulator's effect is dependent on the presence and concentration of endogenous ligands. This creates a self-regulating system that automatically adjusts receptor activation levels based on physiological conditions, preventing both under- and over-activation, thereby improving the safety profile while maintaining therapeutic efficacy.

Inventive Principle:

Principle #23Feedback

3Reliability

If existing medications for cardiovascular disorders are used, then treatment is provided, but efficacy is inadequate and side effects are prominent

Engineering Contradiction:

Improvetreatment effectivenessVSAvoidside effects and inadequate efficacy

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the fundamental parameter of receptor interaction from orthosteric competition to allosteric modulation. This parameter change transforms the mode of action from direct agonism with fixed efficacy to modulatory action with flexible, context-dependent effects. The allosteric modulators can enhance endogenous ligand effects without completely overriding physiological regulation, providing improved efficacy with a more favorable side effect profile compared to conventional medications.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS11472803B27-substituted 1-aryl-naphthyridine-3-carboxylic acid amides and use thereof

Publication Date: 2022.10.18 BAYER AG

AI summary

The present application relates to novel 7-substituted 1-arylnaphthyridine-3-carboxamides, to processes for their preparation, to their use, alone or in combinations, for the treatment and/or prevention of diseases, and to their use for the production of medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular disorders and/or renal disorders.