Pyridine Pyrazine Triazine Compounds as Allosteric SHP2 Inhibitors
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Solution Overview
Problem
Current therapies lack effective small molecules to inhibit the activity of SHP2, a protein tyrosine phosphatase implicated in various diseases such as Noonan Syndrome, leukemia, and cancers, highlighting a need for targeted therapeutic agents.
Innovation Solution
Development of compounds of specific formulas (Ia, I, IIa, IIb, III, IV, V, VI) that inhibit SHP2 activity, including pharmaceutically acceptable salts, prodrugs, solvates, hydrates, and isomers, for use in treating diseases associated with aberrant SHP2 modulation.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If small molecule inhibitors are developed to target SHP2, then therapeutic efficacy for diseases associated with SHP2 aberration is improved, but the complexity of compound structure and synthesis increases
Solution Approach 1:
The patent divides the inhibitor molecules into multiple structural components with specific functions: a core scaffold (pyridine, pyrazine, or triazine ring system) that provides the basic pharmacological activity, and various substituent groups (R1-R6, X1-X3, Y1) that modulate binding affinity and selectivity. This segmentation allows systematic optimization of therapeutic efficacy while managing structural complexity through modular design.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters such as substituent types, positions, and configurations on the core scaffold. By changing these parameters (e.g., different R1-R6 groups, X1-X3 atoms, Y1 linkages), the invention optimizes binding affinity and selectivity for SHP2 while maintaining manageable synthesis complexity through established chemical modification approaches.
2Adaptability or versatility
If multiple compound formulas are developed to inhibit SHP2, then treatment options for various diseases are expanded, but the difficulty of synthesizing these compounds increases
Solution Approach 1:
The patent creates a universal core scaffold system (pyridine, pyrazine, or triazine rings with common substitution patterns) that can generate multiple active compounds through systematic substitution. This universal framework provides versatility for treating different diseases associated with SHP2 aberration while simplifying synthesis by using a common starting material and standardized substitution reactions rather than requiring entirely separate synthesis routes for each compound.
Solution Approach 2:
The patent employs preliminary action by establishing the core scaffold structure first, then performing sequential substitution steps to generate the final compounds. This approach simplifies synthesis by preparing the fundamental pharmacological unit before adding functional groups, making the overall manufacturing process more efficient and scalable compared to synthesizing each compound from scratch.
Data Source
AI summary
The present disclosure is directed to inhibitors of SHP2 and their use in the treatment of disease. Also disclosed are pharmaceutical compositions comprising the same.