Indole Compounds Down-Regulating Estrogen Receptors
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Solution Overview
Problem
Current therapies for ER-positive breast cancers, such as tamoxifen and fulvestrant, face challenges with de novo resistance and limited efficacy due to receptor mutations and pharmacological limitations, necessitating new agents that can effectively down-regulate estrogen receptors.
Innovation Solution
Development of specific indole compounds and their pharmaceutically acceptable salts that selectively down-regulate estrogen receptors, exhibiting potent anti-tumor activity and improved pharmaceutical properties compared to existing SERDs.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies such as tamoxifen and fulvestrant are used to treat ER-positive breast cancer, then anti-tumor activity is achieved, but de novo resistance develops and efficacy is limited due to receptor mutations and pharmacological limitations
Solution Approach 1:
The patent employs parameter changes by modifying the chemical structure of fulvestrant to create novel indole compounds with improved pharmacological properties. The compounds of Formula (I) introduce various substituents (R1-R11) that alter binding affinity, receptor down-regulation efficiency, and pharmacokinetic parameters, thereby overcoming resistance while maintaining anti-tumor activity
Solution Approach 2:
The invention creates composite molecular structures by combining the fulvestrant scaffold with additional functional groups and moieties. The compounds integrate multiple pharmacophores including the indole core, substituted phenyl groups, and various alkyl/alkenyl chains, forming composite molecules that simultaneously achieve high ER down-regulation and improved pharmacokinetic profiles
2Reliability
If estrogen receptors are down-regulated to treat breast cancer, then anti-tumor activity increases, but receptor mutations reduce the effectiveness of existing SERDs
Solution Approach 1:
The patent applies local quality by introducing specific substituents at defined positions on the indole scaffold that selectively enhance binding to wild-type ER while maintaining or improving activity against mutant ER. The strategic placement of fluorinated alkyl groups, aromatic substituents, and heteroatomic groups creates localized interactions that overcome mutation-induced resistance
3Reliability
If new indole compounds are developed to overcome resistance, then therapeutic benefits are improved, but pharmaceutical properties and synthesis complexity must be optimized
Solution Approach 1:
The patent employs segmentation by dividing the complex indole molecule into modular components that can be synthesized separately and assembled. The core indole structure, substituted phenyl groups, and side chains are developed as independent synthetic building blocks, allowing parallel synthesis and simplifying the overall manufacturing process while maintaining the complex pharmacological profile
Data Source
AI summary
The specification relates to compounds of Formula (I):and pharmaceutically acceptable salts thereof, to processes and intermediates used for their preparation, pharmaceutical compositions containing them and their use in the treatment of cell proliferative disorders.