Quinoline RET Inhibitors for Potency and Pharmacokinetic Stability
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Solution Overview
Problem
Current treatments for RET-related tumors and intestinal diseases related to abnormal activation of the RET kinase lack effective and selective inhibitors.
Innovation Solution
Development of quinoline derivatives that act as RET inhibitors, including various geometric and stereoisomers and their pharmaceutically acceptable salts, which exhibit strong inhibitory effects on both wild-type and V804M mutant RET kinases, with improved metabolic stability, safety, and pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If selective RET inhibitors are developed for treating RET-related tumors, then treatment efficacy is improved, but metabolic stability and pharmacokinetic properties need to be optimized simultaneously
Solution Approach 1:
The patent systematically varies chemical parameters including substituent types (R1-R19), linker groups (L), ring structures (R18), and positional isomers to optimize both RET inhibition efficacy and metabolic stability. This structure-activity relationship optimization allows simultaneous improvement of treatment efficacy and pharmacokinetic properties
Solution Approach 2:
The invention creates composite molecular structures combining quinoline core with various heterocyclic groups (piperazinyl, piperidinyl, 3,6-diazabicyclo-[3.3.1]heptanyl) and substituted aromatic rings. These composite structures achieve both strong RET kinase binding and improved metabolic stability through strategic molecular design
2Reliability
If quinoline derivatives are designed with multiple substituents to enhance RET inhibition, then inhibitory effect is improved, but molecular complexity increases
Solution Approach 1:
The molecule is segmented into distinct functional modules: a quinoline core, heterocyclic groups (R18), aromatic substituents (R1-R19), and linker groups (L). Each segment can be independently optimized for its specific function while maintaining overall molecular manageability and synthetic accessibility
Solution Approach 2:
The quinoline derivative structure serves multiple functions simultaneously: the quinoline core provides RET kinase binding, heterocyclic groups enhance selectivity, aromatic substituents optimize pharmacokinetic properties, and linker groups provide structural flexibility. This multi-functionality reduces the need for separate molecular components
Data Source
AI summary
Disclosed are a class of compounds represented by formula (II), and isomers or pharmaceutically acceptable salts thereof.