Branched 3-Phenylpropionic Acid Derivatives for 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 activators for the haem-free form of soluble guanylate cyclase.
Innovation Solution
Development of novel 3-phenylpropionic acid derivatives that directly activate the haem-free form of soluble guanylate cyclase, offering a NO-independent and haem-independent mechanism of action, which can be used to treat cardiovascular disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If NO-based compounds are used to stimulate soluble guanylate cyclase, then cardiovascular disorders can be treated, but tolerance develops and side effects occur
Solution Approach 1:
The patent introduces a novel intermediary mechanism by using compounds that directly activate soluble guanylate cyclase without requiring NO as an intermediate. The compounds of formula (I) bind to and activate sGC directly, bypassing the NO-cGMP pathway that causes tolerance, thus maintaining therapeutic effectiveness while eliminating the harmful effects of NO-based treatments
Solution Approach 2:
The invention changes the fundamental activation parameter of soluble guanylate cyclase from NO-dependent to direct ligand-dependent activation. By modifying the activation mechanism parameter rather than adjusting NO dosage, the patent eliminates tolerance development and side effects while preserving the therapeutic benefit of cGMP elevation
2Adaptability or versatility
If haem-containing soluble guanylate cyclase is targeted, then NO-independent activation is achieved, but haem-free form cannot be activated
Solution Approach 1:
The patent creates a universal activator that functions across different enzymatic states. The compounds of formula (I) are designed to activate both haem-containing and haem-free forms of soluble guanylate cyclase, making the therapy effective regardless of the enzyme's haem status. This multi-functionality ensures reliable activation in various pathological conditions where haem may be depleted or modified
Solution Approach 2:
Instead of designing compounds that require haem as a cofactor for activation, the invention inverts the approach by creating ligands that can activate the enzyme in both haem-containing and haem-free states. This inversion of the activation requirement ensures broader applicability and reliability across different physiological and pathological conditions
3Ease of operation
If existing sGC activators are used, then NO-independent activation is achieved, but they require haem to be present
Solution Approach 1:
The compounds of formula (I) are designed with universal activation capability, functioning whether haem is present or absent. This eliminates the limitation of existing activators that only work with haem-containing enzyme, thereby improving adaptability to various pathological states while maintaining the simplicity of direct activation
Data Source
AI summary
The present application relates to novel 3-phenylpropionic acid derivatives which carry a branched or cyclic alkyl substituent in the 3-position, 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 diseases.