Pyrimidinone Derivatives as Selective SHP2 Inhibitors
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Solution Overview
Problem
Current SHP2 inhibitors, such as SHP099 and RMC-4550, lack selectivity over hErg, leading to potential cardiotoxicity and suboptimal pharmacokinetic properties, necessitating the development of more effective and safer SHP2 inhibitors for treating hyperproliferative diseases.
Innovation Solution
Pyrimidinone derivatives are developed as highly selective SHP2 inhibitors, exhibiting improved safety profiles and pharmacokinetic properties, including lower IC50 values, to effectively target SHP2 and ERK1/2, thereby treating hyperproliferative diseases like cancer with reduced cardiotoxic risk.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current SHP2 inhibitors (SHP099, RMC-4550) are used, then SHP2 inhibition is achieved, but selectivity over hErg is lost leading to cardiotoxicity
Solution Approach 1:
The patent applies local quality by introducing specific substituent patterns at defined positions on the pyrimidinone core structure. Different R1-R6 groups are strategically placed to create localized interactions that enhance SHP2 binding while avoiding hErg binding, achieving selectivity through localized structural modifications rather than global changes
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters such as substituent types, positions, and molecular properties of the pyrimidinone derivatives. This includes adjusting electronic properties, steric characteristics, and hydrophobicity to optimize SHP2 inhibition while eliminating cardiotoxic effects through precise parameter control
2Reliability
If current SHP2 inhibitors are used, then target engagement is achieved, but pharmacokinetic properties are suboptimal
Solution Approach 1:
The patent optimizes pharmacokinetic parameters by modifying molecular weight, lipophilicity, hydrogen bonding capacity, and metabolic stability of the pyrimidinone derivatives. These parameter changes improve oral bioavailability, half-life, and tissue distribution while maintaining effective target engagement at lower doses
3Object-affected harmful factors
If pyrimidinone derivatives are designed for high SHP2 selectivity, then safety is improved, but IC50 values must be optimized
Solution Approach 1:
The patent achieves both safety and potency by introducing specific functional groups at strategic positions on the pyrimidinone core. These localized modifications create selective interactions with SHP2 active site residues while maintaining high binding affinity, evidenced by low IC50 values in the nanomolar range
Solution Approach 2:
The patent creates composite molecular structures combining the pyrimidinone core with various aromatic, heterocyclic, and aliphatic substituents. This composite approach allows independent optimization of selectivity (through core structure) and potency (through substituent properties), achieving both safety and efficacy
Data Source
AI summary
The invention relates to pyrimidinone derivatives of the general Formula I,or a pharmaceutically acceptable salt thereof, and the use of the compounds of the present invention for the treatment of hyperproliferative diseases and disorders in mammals, especially humans, and pharmaceutical compositions containing such compound.