Isoquinoline Derivatives Inhibit Rho-kinase Specificity

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Solution Overview

Problem

Current treatments for diseases related to Rho-kinase activity, such as hypertension and cardiovascular disorders, lack effective inhibitors that can specifically target Rho-kinase and its mediated phosphorylation of myosin light chain phosphatase.

Innovation Solution

Development of novel isoquinoline and isoquinolinone derivatives that act as inhibitors of Rho-kinase, specifically designed to target and inhibit the Rho-kinase mediated phosphorylation of myosin light chain phosphatase, offering a therapeutic approach for various cardiovascular and non-cardiovascular diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current treatments for Rho-kinase related diseases are used, then existing therapeutic options are available, but effective and specific Rho-kinase inhibitors are lacking

Engineering Contradiction:

Improveeffectiveness of treatmentVSAvoidavailability of specific inhibitors

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent segments the Rho-kinase enzyme into specific binding pockets and interaction regions, designing compounds that target distinct portions of the enzyme. The isoquinoline and isoquinolinone derivatives are structured to interact with specific amino acid residues in the Rho-kinase active site, allowing for selective inhibition of Rho-kinase isoforms while sparing other kinases.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent systematically varies key molecular parameters of the isoquinoline and isoquinolinone core structures, including substituent types at positions 1, 2, 3, 4, 5, 6, 7, and 8, as well as variations in ring saturation and oxidation states. These parameter changes optimize binding affinity and selectivity for Rho-kinase while maintaining drug-like properties.

Inventive Principle:

Principle #35Parameter changes

2Adaptability or versatility

If Rho-kinase activity is inhibited, then diseases like hypertension and cardiovascular disorders can be treated, but specificity in targeting Rho-kinase mediated phosphorylation is required

Engineering Contradiction:

Improvetherapeutic applicabilityVSAvoidspecificity of inhibition

Core Design Contradiction:

Adaptability or versatilityVSMeasurement precision

Solution Approach 1:

The patent introduces local quality variations through specific substituent patterns on the isoquinoline and isoquinolinone rings. Electron-withdrawing and electron-donating groups are strategically placed to modulate the electronic properties of the core structure, enhancing interactions with specific amino acid side chains in the Rho-kinase binding pocket while avoiding off-target kinase inhibition.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs asymmetric substitution patterns on the isoquinoline and isoquinolinone cores, creating chiral centers and diastereomers with distinct spatial arrangements. This asymmetry allows for selective recognition of the asymmetric Rho-kinase binding site, improving specificity while enabling optimization of pharmacokinetic properties through selection of specific stereoisomers.

Inventive Principle:

Principle #4Asymmetry

Data Source

PatentEP2102187B1Substituted isoquinoline and isoquinolinone derivatives as inhibitors of rho-kinase

Publication Date: 2015.04.01 SANOFI SA(FR)

AI summary

The invention relates to 6-substituted isoquinoline and isochinolone derivatives of the formula (I) useful for the treatment and/or prevention of diseases associated with Rho-kinase and/or Rho-kinase mediated phosphorylation of myosin light chain phosphatase, and compositions containing such compounds.