Indole ER Antagonists With Improved Oral Bioavailability
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Solution Overview
Problem
Current treatments for estrogen receptor positive breast cancer, particularly those resistant to aromatase inhibitors, face challenges due to poor pharmacokinetics and tissue distribution issues, leading to incomplete degradation of mutant estrogen receptors and limited clinical efficacy.
Innovation Solution
Development of novel indole compounds and their pharmaceutically acceptable salts that act as estrogen receptor antagonists, designed to improve pharmacokinetic properties and target mutant estrogen receptors effectively.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If fulvestrant is administered by intramuscular injection to treat AI-resistant ER mutant breast cancer, then it can achieve some therapeutic effect, but it has poor pharmacokinetics with zero bioavailability via oral administration and high blood clearance rate
Solution Approach 1:
The patent modifies the chemical structure of fulvestrant by introducing a hydrophilic group at the C-17 beta position, changing the pharmacokinetic parameters of the drug. This structural modification enables the drug to achieve systemic exposure after oral administration and reduces blood clearance rate, thereby improving pharmacokinetics while maintaining therapeutic effect.
2Reliability
If fulvestrant is administered by intramuscular injection, then it can be delivered systemically, but its strong lipophilicity causes serious problems in tissue distribution
Solution Approach 1:
By introducing a hydrophilic group at the C-17 beta position, the patent changes the lipophilicity parameter of fulvestrant. This modification improves tissue distribution by reducing excessive lipophilicity, allowing the drug to achieve better balance between systemic delivery and tissue penetration.
3Reliability
If the current approved dosage of fulvestrant is used, then it can be administered safely, but it cannot cause complete degradation of ER, especially mutant ER, at tissue concentration
Solution Approach 1:
The patent modifies the chemical structure to enhance the drug's ability to degrade ER at tissue concentrations. The structural change at C-17 beta position improves the drug's affinity and efficacy toward mutant ER, enabling complete degradation at safer, lower doses.
4Reliability
If letrozole is used as first-line endocrine therapy, then it demonstrates good efficacy in treating estrogen receptor positive breast cancer, but resistance problem develops over time
Solution Approach 1:
The patent develops a modified fulvestrant derivative that acts as an intermediary therapy after AI resistance develops. The drug introduces a new mechanism of action (enhanced ER degradation via C-17 beta modification) that overcomes the resistance mechanism developed against AIs, extending the duration of endocrine therapy response.
Data Source
AI summary
Provided is an indole compound. In particular, disclosed are a compound represented by formula (II) or an isomer or pharmaceutically acceptable salt thereof and a use of the same as an estrogen receptor antagonist in preparing a drug for treating estrogen receptor-positive breast cancer.