Heterocyclic Compounds Modulating MAPK Kinase Activity
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Solution Overview
Problem
Current treatments for cancer and other diseases related to deregulated kinases, such as those in the MAPK pathway, lack specific and potent chemical structures that can modulate protein kinase activity effectively.
Innovation Solution
Development of heterocyclic compounds, including derivatives of benzotriazine and bridged benzene-heterocyclic structures, which can inhibit kinase activity in the MAPK signaling pathway, offering potential therapeutic benefits as pharmaceutical compositions for various diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemical structures are used to treat cancer and diseases related to deregulated kinases, then treatment options are available, but the treatments lack specificity and potency in modulating protein kinase activity
Solution Approach 1:
The patent applies local quality by designing heterocyclic compounds with specific functional groups and structural features that target particular regions of the kinase catalytic domain. The compounds contain heteroatoms (nitrogen, oxygen, sulfur) at specific positions within the ring structure, creating localized chemical properties that enhance binding affinity and selectivity for specific kinase isoforms while maintaining broad applicability across different disease states.
Solution Approach 2:
The patent employs parameter changes by systematically varying structural parameters of the heterocyclic compounds, including ring size, heteroatom composition, substituent types, and molecular weight. These parameter modifications allow optimization of both specificity (through precise molecular recognition) and versatility (through adaptable binding to different kinase targets), resolving the contradiction between targeted action and broad therapeutic applicability.
2Reliability
If small molecules are designed to bind to kinase catalytic domain to inhibit signaling pathways, then protein kinase activity can be modulated, but achieving high selectivity and potency within a practical therapeutic window remains challenging
Solution Approach 1:
The patent uses the heterocyclic ring structure as an intermediary element that mediates between the drug molecule and the kinase target. The heterocyclic core provides a balanced level of complexity - sufficiently complex to achieve high selectivity through specific molecular interactions, yet not overly complex to maintain drug-like properties and practical therapeutic windows. The heteroatoms in the ring structure act as intermediaries for forming specific hydrogen bonds and electrostatic interactions with kinase residues.
Solution Approach 2:
The patent applies composite material principles by combining the heterocyclic core structure with various substituent groups (aromatic rings, alkyl chains, functional groups) to create composite molecular structures. This composite approach allows optimization of selectivity through the heterocyclic core while adjusting potency and pharmacological properties through the attached substituents, achieving high selectivity and potency without excessive overall molecular complexity.
Data Source
AI summary
Heterocyclic compounds derived from benzotriazine, triazines, triazoles and oxadiazoles are disclosed. The methods of synthesis and of use of such heterocyclic compounds are also provided.