6-Substituted Isoquinolines for Rho-Kinase Selectivity
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Solution Overview
Problem
Current Rho-kinase inhibitors lack selectivity against other kinases, which limits their therapeutic efficacy in treating Rho-kinase mediated diseases.
Innovation Solution
Development of novel isoquinoline and isoquinolinone derivatives with specific substituents that provide improved selectivity against other kinases, formulated as compounds of a particular structure to inhibit Rho-kinase and its mediated phosphorylation of myosin light chain phosphatase.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current Rho-kinase inhibitors are used, then they can inhibit Rho-kinase activity, but they lack selectivity against other kinases which limits therapeutic efficacy
Solution Approach 1:
The patent applies local quality by introducing specific substituent groups at defined positions (R1-R15) of the isoquinoline/isoquinolinone core structure. Each substituent position can be independently optimized to enhance binding affinity for Rho-kinase while maintaining selectivity against other kinases, allowing localized modification of molecular properties to achieve the desired selectivity-efficacy balance
Solution Approach 2:
The patent employs parameter changes by systematically varying substituent types, positions, and configurations (R1-R15) to optimize the compound's kinetic parameters for Rho-kinase inhibition. By adjusting these molecular parameters, the invention achieves improved selectivity and therapeutic efficacy compared to prior art inhibitors
2Reliability
If novel isoquinoline and isoquinolinone derivatives with specific substituents are developed, then selectivity against other kinases is improved, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the molecule into a core isoquinoline/isoquinolinone structure and multiple independent substituent positions (R1-R15). This modular approach allows systematic optimization of selectivity at each position while maintaining a manageable overall structural framework, reducing the complexity burden of achieving high selectivity
Solution Approach 2:
The patent employs universality by designing a core isoquinoline/isoquinolinone scaffold that provides universal Rho-kinase binding capability, while variable substituents (R1-R15) can be adjusted to achieve specific selectivity profiles. This multi-functional design allows the same core structure to serve as a platform for generating multiple selective inhibitors with different therapeutic applications
Data Source
AI summary
The invention relates to 6-substituted isoquinoline and isoquinolinone 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.