Fluorinated Vinyl-N-Propyl Pyrrolidine SERDs for ERα Resistance
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Solution Overview
Problem
Existing endocrine therapies for ERα-positive breast cancer, such as aromatase inhibitors, tamoxifen, and fulvestrant, face challenges with de novo resistance and acquired mutations in estrogen receptors, necessitating the development of more effective Selective Estrogen Receptor Degraders (SERDs) to counteract hormone-independent signaling.
Innovation Solution
Development of novel fluorinated vinyl-N-propyl-pyrrolidine derivatives that selectively antagonize and degrade estrogen receptors, providing a new strategy to inhibit ERα signaling in cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing endocrine therapies (aromatase inhibitors, tamoxifen, fulvestrant) are used to treat ERα-positive breast cancer, then cancer treatment is provided, but resistance develops over time or de novo resistance occurs in about one-third of patients
Solution Approach 1:
The patent modifies the molecular structure of pyrrolidine derivatives by introducing fluorine atoms at specific positions (R4 and/or R4') to enhance binding affinity and degradation efficacy. This parameter change in molecular composition enables the compounds to overcome resistance mechanisms while maintaining therapeutic effectiveness.
Solution Approach 2:
The invention creates composite molecular structures combining fluorinated pyrrolidine cores with various aromatic substituents (phenyl, heteroaryl, carbonyl groups). These composite structures provide multiple interaction sites for degrading ERα receptors, thereby improving therapeutic reliability and extending the duration of action.
2Reliability
If Selective Estrogen Receptor Degraders (SERDs) are developed to counteract hormone-independent signaling, then resistance to current therapies can be overcome, but the complexity of compound synthesis increases
Solution Approach 1:
The patent divides the synthesis process into modular steps: (1) preparation of the fluorinated pyrrolidine core, (2) introduction of aromatic substituents through coupling reactions, and (3) final functional group modifications. This segmentation allows for systematic optimization of degradation efficacy while managing synthesis complexity through standardized protocols.
Solution Approach 2:
The invention optimizes synthesis parameters such as reaction conditions, catalysts, and reagents to improve efficiency. By controlling parameters like temperature, solvent choice, and stoichiometry, the patent reduces the complexity of multi-step synthesis while maintaining high degradation efficacy.
3Reliability
If fluorinated vinyl-N-propyl-pyrrolidine derivatives are synthesized with specific substituents (R1-R9, X, m, n, Y), then binding affinity to estrogen receptors is enhanced, but the number of possible compounds and synthesis routes increases
Solution Approach 1:
The patent applies local quality by introducing fluorine atoms at specific positions (R4 and/or R4') and attaching aromatic groups at defined locations on the pyrrolidine ring. This localized modification strategy enhances binding affinity at critical interaction sites while maintaining a manageable framework for structural variation.
Solution Approach 2:
The fluorinated pyrrolidine core serves as a universal scaffold that can accommodate multiple aromatic substituents (phenyl, heteroaryl, carbonyl groups) at different positions. This multi-functional scaffold approach allows a single core structure to generate multiple active compounds with optimized binding affinity for different ERα mutations and resistance profiles.
Data Source
AI summary
Disclosed herein are compounds of the formula (I), or pharmaceutically acceptable salts thereof, wherein R1 and R2 represent hydrogen or deuterium; R3 represents hydrogen, —COOH or —OH; R3′ and R3″ represent hydrogen, methyl, methoxy, chlorine, fluorine or cyano; R4 and R4′ represent hydrogen or fluorine; R5 represents hydrogen, fluorine or (C1-C3)alkyl; R6 represents phenyl, fused phenyl, bicyclic group comprising 5 to 12 carbon atoms, heteroaryl group comprising 2 to 9 carbon atoms and comprising from 1 to 3 heteroatoms, cycloalkyl group comprising 3 to 7 carbon atoms, (C3-C6)cycloalkyl(C1-C3)alkyl group, 4 to 7 membered-heterocycloalkyl group comprising 1 or 2 heteroatoms, (C1-C6)alkyl, and phenyl(C1-C2)alkyl group; X represents —CH2—, —O— or —S—; Y represents —CH═, —N═ or —CR″═, wherein R″ represents (C1-C3)alkyl, halogen, cyano, or (C1-C3)fluoroalkyl; R7 represents (C1-C3)alkyl, halogen atom, cyano, or (C1-C3)fluoroalkyl; R8 represents hydrogen or fluorine; R9 represents hydrogen, (C1-C3)alkyl or a cyclopropyl; n is 0, 1 or 2; and m is 0 or 1. Further disclosed are process for preparing the same, pharmaceutical compositions comprising them as well as said compounds of formula (I) for use as an inhibitor and degrader of estrogen receptors, in particular in the treatment of ovulatory dysfunction, cancer, endometriosis, osteoporosis, benign prostatic hypertrophy or inflammation.