Selective ERα/ERβ Ligands With Minimal GPER Cross-Reactivity
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Solution Overview
Problem
Current treatments for diseases mediated through estrogen receptors alpha and beta lack specificity, often affecting GPER receptors and leading to unintended side effects.
Innovation Solution
Development of 3-oxabicyclo[3.3.1]nonene derivatives that selectively bind to ERalpha and/or ERbeta, acting as agonists or antagonists, and can be labeled with fluorescent dyes or radionuclides for diagnostic and therapeutic applications.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for diseases mediated through estrogen receptors are used, then therapeutic effects are achieved, but cross-reactivity with GPER receptors causes unintended side effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (3-oxabicyclo[3.3.1]nonene core with particular substituent patterns at positions 2, 4, 5, 6, and 7) that create selective binding affinity for ERα and/or ERβ receptors while minimizing interaction with GPER receptors. This structural differentiation enables the compound to target specific receptor subtypes with distinct pharmacological properties, thereby achieving therapeutic effects with reduced off-target side effects
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters including substituent types (halogens, hydroxyl groups, alkyl chains), substituent positions, and molecular stereochemistry to optimize the compound's binding characteristics. By adjusting these chemical parameters, the invention achieves selective agonist or antagonist activity at ERα and/or ERβ while maintaining low affinity for GPER, thus resolving the contradiction between therapeutic efficacy and side effect profile
2Adaptability or versatility
If compounds with broad estrogen receptor activity are used, then multiple disease pathways are addressed, but specificity for target receptors decreases
Solution Approach 1:
The patent applies segmentation by dividing the estrogen receptor target space into distinct segments (ERα, ERβ, and GPER) and designing compounds that selectively interact with specific segments. The 3-oxabicyclo[3.3.1]nonene core structure with tailored substituents enables the compound to segment its pharmacological activity, providing selective modulation of ERα and/or ERβ while excluding GPER, thus achieving both versatility in treating ER-mediated diseases and precision in receptor binding
3Reliability
If selective ERalpha/ERbeta compounds are developed, then cross-reactivity with GPER is reduced, but compound complexity increases
Solution Approach 1:
The patent applies the taking out principle by extracting the essential pharmacophore elements required for ERα and/or ERβ binding from complex estrogenic molecules and incorporating them into a simplified 3-oxabicyclo[3.3.1]nonene core structure. By taking out only the critical binding features and removing unnecessary complexity, the invention achieves selective ERα/ERβ activity with a relatively compact and synthetically accessible molecular framework
Solution Approach 2:
The patent employs composite materials by combining the 3-oxabicyclo[3.3.1]nonene core structure with specific functional substituents (such as hydroxyl groups, halogen atoms, and alkyl chains) to create a composite molecular architecture. This composite structure integrates the scaffold that provides selective receptor binding with substituents that fine-tune pharmacological properties, achieving high selectivity for ERα and/or ERβ while maintaining reasonable structural complexity
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
These derivatives provide targeted treatment options for various diseases, including cancer and hormone-related disorders, with reduced side effects by minimizing cross-reactivity with GPER receptors.
Implementation Method 1
novel 3-oxabicyclo[3.3.1]nonene derivatives that selectively bind to ERα and/or ERβ... These compounds may function as agonists and/or antagonists of one or more of the disclosed estrogen receptors
Implementation Method 2
3-oxabicyclo[3.3.1]nonene derivatives labeled with fluorescent dyes for in vitro and in vivo applications
Implementation Method 3
3-oxabicyclo[3.3.1]nonene derivatives that are directly labeled with stable isotope or radionuclides for analytical, diagnostic and/or therapeutic applications
Data Source
AI summary
The current invention is in the field of molecular biology/pharmacology and provides novel 3-oxabicyclo[3.3.1]nonene compounds and derivatives that modulate the effects of the classical estrogen receptors alpha and beta (ERalpha and ERbeta) with little to no biological or physiological effects on the G protein-coupled estrogen receptor GPER (also known as GPR30). These compounds may function as agonists and/or antagonists of one or more of the disclosed classical estrogen receptors. Diseases that are mediated through one or more of these receptors are described. A contraceptive indication to prevent or reduce the likelihood of pregnancy after intercourse is a further aspect of the present invention.