Isoindoline Derivative TNF-α Regulation Side Effects
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Solution Overview
Problem
Lenalidomide, a drug used to regulate TNF-α activity, has significant side effects such as myelosuppression, deep vein thrombosis, and teratogenesis, limiting its efficacy due to hematologic toxicity, necessitating the development of improved isoindoline derivatives with enhanced performance.
Innovation Solution
An isoindoline derivative represented by general formula (I), along with its pharmaceutically acceptable salts, solvates, polymorphs, stereoisomers, and isotopic compounds, is synthesized to regulate cytokine production, specifically TNF-α, for treating cancers and inflammatory diseases with reduced side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If Lenalidomide is used to regulate TNF-α activity, then the therapeutic effect on cancers and inflammatory diseases is improved, but significant side effects such as myelosuppression, deep vein thrombosis, and teratogenesis occur
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of Lenalidomide through systematic variations in the isoindoline core structure, substituent groups, and molecular configuration. These structural parameter changes result in derivatives that maintain TNF-α regulatory activity while reducing hematologic toxicity and other adverse effects, thereby improving the therapeutic index
Solution Approach 2:
The patent applies local quality by introducing specific substituent groups at particular positions on the isoindoline structure. Different substituents (such as halogens, alkyl groups, alkoxy groups, and heterocyclic groups) are placed at specific locations to modulate local molecular properties, which in turn affects the drug's interaction with biological targets and reduces specific side effects while preserving therapeutic activity
2Reliability
If Lenalidomide is administered at higher doses to overcome hematologic toxicity, then the therapeutic potency is improved, but the occurrence of side effects increases
Solution Approach 1:
The patent employs parameter changes by systematically varying molecular weight, lipophilicity, and structural configuration of the isoindoline derivatives. These parameter modifications enable the development of compounds with improved potency-to-toxicity ratios, allowing effective TNF-α regulation at doses that do not provoke severe hematologic toxicity
Data Source
AI summary
Provided are an isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof. The isoindoline derivative and the pharmaceutical composition thereof can regulate the production or activity of immunological cytokines, thus effectively treating cancer and inflammatory disease.