Pyrrolidine SERD Composition for Oral Brain-Penetrant ER Degradation

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Solution Overview

Problem

Current treatments for estrogen receptor-positive breast cancer, particularly those using fulvestrant, face challenges such as drug resistance, limited bioavailability, slow absorption, inability to permeate the blood-brain barrier, and adverse reactions, which hinder effective treatment of ER-positive breast cancer, especially brain metastases.

Innovation Solution

Development of a novel pyrrolidine compound or its pharmaceutically acceptable salt, designed to selectively degrade estrogen receptors, offering high bioavailability, blood-brain barrier permeability, and oral administration, thereby inhibiting tumor growth and improving survival in ER-positive breast cancer models.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If fulvestrant is used as a SERD drug for treating ER-positive metastatic breast cancer, then ER degradation is achieved, but the drug cannot permeate through the blood-brain barrier and has limited exposure in the body

Engineering Contradiction:

ImproveER degradation efficacyVSAvoidlimited bioavailability and blood-brain barrier permeability

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent modifies the chemical structure of fulvestrant by introducing a pyrrolidine ring and various substituents (R1-R6, X1-X4, Y, Z) to change the pharmacokinetic parameters of the drug. These structural modifications enable the compound to permeate the blood-brain barrier while maintaining ER degradation activity, thereby improving bioavailability and central nervous system exposure without sacrificing therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

2Reliability

If intramuscular injection is used for fulvestrant administration, then ER degradation is achieved, but obvious adverse reactions occur at the injection site and absorption is slow

Engineering Contradiction:

ImproveER degradation efficacyVSAvoidpain, swelling, and redness at injection site

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent replaces the mechanical injection route with oral administration capability through chemical structure modification. The pyrrolidine compound can be administered orally and achieves systemic absorption without causing local injection site reactions, while maintaining the ability to degrade ER and treat metastatic breast cancer

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Reliability

If high dose fulvestrant is administered to overcome limited exposure, then ER degradation may be improved, but the maximum dose is limited by intramuscular route constraints

Engineering Contradiction:

ImproveER degradation efficacyVSAvoidmaximum dose limitation

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent changes the pharmacokinetic parameters through structural modification to enable higher effective doses to be achieved via oral administration. The modified compound has improved bioavailability and distribution characteristics that allow sufficient drug exposure at therapeutic doses without being constrained by the 500 mg maximum intramuscular injection limit

Inventive Principle:

Principle #35Parameter changes

4Ease of operation

If standard endocrine therapy is continued for relapsed patients, then treatment simplicity is maintained, but acquired drug resistance causes treatment failure

Engineering Contradiction:

Improvetreatment continuityVSAvoidtreatment efficacy

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

The patent inverts the mechanism of action from simple ER modulation (SERMs) or ER downregulation (fulvestrant) to a novel pyrrolidine-based SERD that can overcome ESR1 mutations and acquired resistance. This new compound class targets the mutated ER variants that standard therapies cannot effectively address, restoring treatment efficacy in relapsed and resistant patients

Inventive Principle:

Principle #13The other way round (Inversion)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The compound demonstrates significant antitumor activity in vitro and in vivo, inhibiting ER-positive breast cancer growth, including brain metastases, with improved survival rates and potential for effective treatment through oral administration.

Implementation Method 1

designed to selectively degrade estrogen receptors, offering high bioavailability, blood-brain barrier permeability, and oral administration, thereby inhibiting tumor growth

Methodology Applied

Scientific EffectSelective estrogen receptor degradation:

Data Source

PatentUS12570652B2Pyrrolidine compound and use thereof

Publication Date: 2026.03.10 SIMCERE PHARMA CO LTD

AI summary

Disclosed are a pyrrolidine compound as represented by formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing same, and the use of the pharmaceutical composition as a selective estrogen receptor degrader (SERD) in the prevention or treatment of estrogen receptor-related diseases.