3-Phenylpropionic Acid Derivatives for Haem-Free sGC Activation

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Solution Overview

Problem

Current treatments for cardiovascular disorders, particularly those involving the NO/cGMP system, face challenges such as reliance on NO-based compounds that develop tolerance and have side effects, and lack of effective NO-independent activators for soluble guanylate cyclase.

Innovation Solution

Development of novel 3-phenylpropionic acid derivatives that directly activate haem-free soluble guanylate cyclase without synergistic action with NO and are not inhibited by haem-dependent inhibitors, offering a unique binding mechanism to stimulate the enzyme.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If NO-based compounds are used to stimulate soluble guanylate cyclase, then the enzyme activation is achieved, but tolerance develops and side effects occur

Engineering Contradiction:

Improveenzyme activation reliabilityVSAvoidside effects and tolerance

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces a new class of compounds (BAY 41-2272, BAY 41-8543, BAY 63-2521) that act as intermediaries to activate soluble guanylate cyclase through a different mechanism than NO. These compounds bind to a specific site on the enzyme (distinct from the haem binding site) and stimulate catalytic activity without requiring NO binding to haem, thereby achieving enzyme activation while avoiding the harmful effects associated with NO-based therapy

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention changes the activation parameters of soluble guanylate cyclase by using compounds that bind to a non-haem site. This parameter change allows enzyme activation through an alternative pathway that does not involve the traditional NO-haem interaction, thus maintaining therapeutic efficacy while eliminating tolerance and side effects associated with NO-based compounds

Inventive Principle:

Principle #35Parameter changes

2Reliability

If YC-1 and related compounds are used to activate haem-dependent sGC, then selective activation is achieved, but they cannot activate haem-free enzyme

Engineering Contradiction:

Improveselective enzyme activationVSAvoidenzyme form compatibility

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent describes compounds that possess universal activity across different forms of soluble guanylate cyclase. These compounds can activate both haem-containing and haem-free forms of the enzyme, making them more versatile than previous agents like YC-1. This multi-functionality is achieved through a binding mechanism that does not depend on the presence of haem, allowing the compounds to stimulate catalytic activity in both enzyme configurations

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Power

If BAY 58-2667 is used to activate oxidized or haem-free sGC, then high activation is achieved, but it displaces the haem group and requires specific binding site interaction

Engineering Contradiction:

Improveenzyme activation strengthVSAvoidbinding mechanism complexity

Core Design Contradiction:

PowerVSDevice complexity

Solution Approach 1:

The patent introduces compounds with optimized local binding properties that interact with a specific site on soluble guanylate cyclase without displacing the haem group. These compounds have a tailored molecular structure that allows them to bind locally at a defined site (distinct from the haem binding site) and transmit activation signals effectively, achieving high enzyme activation while maintaining simpler and more specific binding interactions compared to BAY 58-2667

Inventive Principle:

Principle #3Local quality

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 effectively activate soluble guanylate cyclase, leading to vasorelaxation, inhibition of platelet aggregation, and blood pressure lowering, with improved pharmacokinetic properties and reduced side effects, making them suitable for treating cardiovascular disorders.

Implementation Method 1

Guanylate cyclases catalyze the biosynthesis of cGMP from guanosine triphosphate (GTP)

Methodology Applied

Scientific EffectEnzyme catalysis: Enzyme

Implementation Method 2

The compounds of the formula (I) and their physiologically compatible salts and solvates are capable of activating the haem-free form of soluble guanylate cyclase

Methodology Applied

Scientific EffectLigand binding:

Implementation Method 3

NO is able to bind to the iron atom of haem and thus markedly increase the activity of the enzyme

Methodology Applied

Scientific EffectMetal coordination:

Implementation Method 4

The soluble guanylate cyclases consist of two subunits and very probably contain one haem per heterodimer, which is part of the regulatory site

Methodology Applied

Scientific EffectEnzyme activation: Enzyme

Implementation Method 5

Carbon monoxide (CO) is also able to attach to the central iron atom of haem, but the stimulation by CO is distinctly less than that by NO

Methodology Applied

Scientific EffectMetal coordination:

Data Source

PatentUS9018414B2Substituted 3-phenylpropionic acids and the use thereof

Publication Date: 2015.04.28 BAYER INTPROP GMBH

AI summary

The present application relates to novel 3-phenylpropionic acid derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular disorders.