Fluorinated N-Propyl Pyrrolidine/Azetidine SERDs for ERα Degradation
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Solution Overview
Problem
Current endocrine therapies for ERα-positive breast cancer, such as tamoxifen and aromatase inhibitors, face significant resistance issues due to ERα mutations, necessitating the development of more effective Selective Estrogen Receptor Degraders (SERDs) that can selectively antagonize and degrade estrogen receptors.
Innovation Solution
Development of novel substituted fluorinated N-propyl-pyrrolidine and N-propyl-azetidine derivatives that act as SERDs, capable of selectively antagonizing and degrading estrogen receptors, particularly targeting ERα to overcome resistance mechanisms in breast cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current endocrine therapies (tamoxifen, aromatase inhibitors) are used to treat ERα-positive breast cancer, then initial treatment effectiveness is achieved, but resistance develops over time due to ERα mutations
Solution Approach 1:
The patent changes the mechanism of action from receptor antagonism to receptor degradation. SERDs induce ubiquitination and proteasomal degradation of ERα, fundamentally altering the therapeutic parameter from blocking signaling to eliminating the receptor protein itself, thereby overcoming mutation-based resistance
Solution Approach 2:
The invention extracts and removes the ERα receptor from the system through degradation. By inducing proteasomal degradation, the therapy physically removes the target receptor from tumor cells, eliminating the basis for resistance that arises from receptor mutations
2Reliability
If SERDs are developed to overcome resistance, then degradation efficacy is improved, but selectivity between ERα and ERβ must be maintained
Solution Approach 1:
The patent applies local quality by designing the SERD molecule with specific structural features that confer preferential binding to ERα over ERβ. The molecular structure contains pharmacophoric elements that interact with ERα-specific binding pockets, creating localized molecular recognition that achieves selectivity
Solution Approach 2:
The invention utilizes asymmetry in the molecular structure of SERDs to differentiate between ERα and ERβ isoforms. The non-symmetric arrangement of functional groups in the SERD molecule creates steric and electronic complementarity specifically with ERα, enabling selective degradation while sparing ERβ
3Reliability
If novel SERD compounds are synthesized to overcome resistance, then therapeutic potential is improved, but complexity of synthesis increases
Solution Approach 1:
The patent segments the SERD molecule into distinct modular components: a steroid core structure, A-ring modifications, and side chain elements. This segmentation allows independent optimization of each module for binding affinity and degradation activity, simplifying the overall synthesis by enabling parallel development of modular building blocks
Solution Approach 2:
The invention employs universal synthetic intermediates and building blocks that can be used across multiple SERD analogs. Common precursors and reaction sequences are developed that can generate families of compounds with different R-groups, reducing overall synthesis complexity through transferable methodology
Data Source
AI summary
Disclosed herein are compounds of the formula (I), or pharmaceutically acceptable salts thereof: wherein R1 and R2 independently represent a hydrogen atom or a deuterium atom; R3 represents a hydrogen atom, a —COOH group or a —OH group; R3′ and R3″ independently represent a hydrogen atom, a methyl group, a methoxy group, a chlorine atom, a fluorine atom, or a cyano group; R4 represents a hydrogen atom or a fluorine atom; R5 and R5′ independently represent a hydrogen atom or a fluorine atom; R6 represents a phenyl group, a fused phenyl group, a bicyclic group comprising 5 to 12 carbon atoms, a heteroaryl group comprising 2 to 9 carbon atoms and comprising from 1 to 3 heteroatoms, a cycloalkyl group comprising 3 to 7 carbon atoms, a (C3-C6)cycloalkyl(C1-C3)alkyl group, a 4 to 7 membered-heterocycloalkyl group, a (C1-C6)alkyl group, or a phenyl(C1-C2)alkyl group; X represents —CH2—, —O— or —S—; Y represents —CH2—, —O— or —NH—; R7 independently represents a (C1-C3)alkyl group, such as a methyl group, a halogen atom, such as a fluorine atom, a cyano group, or a (C1-C3)fluoroalkyl group, such as a trifluoromethyl; R8 represents a hydrogen atom, or a (C1-C3)alkyl group or a cyclopropyl; 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.