Glutamine Analog Composition for Lower GI Toxicity
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Solution Overview
Problem
Glutamine antagonists like 6-diazo-5-oxo-L-norleucine (DON) exhibit severe toxicity, limiting their clinical development due to dose-limiting gastrointestinal issues such as oral mucositis, gastric bleeding, nausea, and abdominal pain, despite their potential anticancer activities.
Innovation Solution
Development of novel glutamine analogs, including compounds of Formula I, their pharmaceutically acceptable salts, stereoisomers, and isotopic substitutions, which are designed to mitigate the severe toxicity associated with existing glutamine antagonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If glutamine antagonists such as DON are administered at therapeutic dose levels to achieve anticancer activity, then anticancer efficacy is improved, but severe gastrointestinal toxicity occurs
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of glutamine antagonists through various substitutions including deuterium atoms, different R1 groups (such as fluorinated alkyl groups, cycloalkyl groups, heterocyclyl groups), and variations in the core molecular framework. These structural parameter changes aim to reduce gastrointestinal toxicity while preserving anticancer activity by altering how the compound interacts with biological systems.
Solution Approach 2:
The patent employs composite material principles by creating complex molecular structures that combine multiple functional groups and substituents on the glutamine antagonist core. These composite structures (with various R1 substitutions including alkoxy, hydroxyl, amino groups, and cyclic structures) are designed to achieve both therapeutic efficacy and reduced toxicity through the synergistic effects of different molecular components.
2Reliability
If the dose of glutamine antagonists is increased to enhance therapeutic effect, then anticancer activity is improved, but dose-limiting side effects increase
Solution Approach 1:
The patent uses parameter changes to modify the molecular parameters of glutamine antagonists, specifically introducing deuterium substitutions, varying R1 group compositions (such as CF3 groups, cyclopropyl, cyclobutyl, pyrrolidinyl groups), and adjusting molecular weight and polarity. These changes aim to improve the therapeutic index by reducing side effects at effective doses.
Solution Approach 2:
The patent applies the principle of using simpler, more stable molecular structures that can be administered at lower doses due to improved pharmacokinetic properties. The modified glutamine analogs with various R1 substitutions are designed to have enhanced stability and reduced metabolism, allowing effective therapy at lower doses with fewer side effects.
Data Source
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AI summary
Glutamine analogs, a composition containing the glutamine analogs and the use thereof.