Substituted Quinazoline Derivatives as DNMT Inhibitors
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Solution Overview
Problem
Current DNA methyltransferase (DNMT) inhibitors, such as nucleoside analogues and non-nucleoside analogues, face limitations including poor bioavailability, instability, and toxicity, necessitating the development of novel DNMT inhibitors for effective cancer treatment.
Innovation Solution
Substituted quinazoline derivatives are developed as DNMT inhibitors, specifically designed to target DNA methylation, offering improved bioavailability and specificity, with potential applications in treating various cancers.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nucleoside analogues or nonnucleoside analogues are used as DNMT inhibitors, then DNMT inhibition activity is achieved, but bioavailability is poor and toxicity is high
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of DNMT inhibitors from traditional nucleoside analogues to quinazoline derivatives with specific substitution patterns. The core quinazoline structure with particular R1-R6 substituents (including options like aryl, heterocycle, alkyl groups) represents a fundamental chemical parameter change that improves the therapeutic index by reducing toxicity while maintaining DNMT inhibition activity.
2Reliability
If nucleoside analogues or nonnucleoside analogues are used as DNMT inhibitors, then DNMT inhibition activity is achieved, but stability is poor
Solution Approach 1:
The patent employs parameter changes by transforming the chemical composition from unstable nucleoside/nonnucleoside analogues to stable quinazoline derivative structures. The specific molecular architecture with fused ring systems and controlled substitution patterns (R1-R6 groups) provides enhanced metabolic and chemical stability while preserving the ability to inhibit DNMT enzymes.
3Reliability
If nucleoside analogues or nonnucleoside analogues are used as DNMT inhibitors, then DNMT inhibition activity is achieved, but bioavailability is poor
Solution Approach 1:
The patent implements parameter changes by optimizing the physicochemical properties of DNMT inhibitors through the quinazoline core structure with specific R1-R6 substituents. This structural transformation improves pharmacokinetic parameters including absorption, distribution, and bioavailability, enabling the drug to reach target tissues effectively while maintaining therapeutic activity.
Data Source
AI summary
The present invention relates to compounds of the following formula (I) and pharmaceutically acceptable salts and solvates thereof, their methods of preparation, their use as a drug, notably in the treatment of cancer, and pharmaceutical compositions containing such compounds.