3-Oxabicyclononene ERα/β Ligands With Minimal GPER Activity
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Solution Overview
Problem
Current treatments for diseases mediated through estrogen receptors alpha and beta lack specificity, often affecting GPER/GPR30 receptors, leading to unintended side effects and reduced efficacy.
Innovation Solution
Development of 3-oxabicyclo[3.3.1]nonene derivatives that selectively bind to ERalpha/beta receptors, 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 they can address the disease conditions, but they lack specificity and affect GPER/GPR30 receptors leading to unintended side effects
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (3-oxabicyclo[3.3.1]nonene derivatives with particular substituent patterns at positions R1-R9) that confer selective affinity for ERα/β receptors over GPER/GPR30. This structural differentiation enables the compound to interact specifically with target receptors while avoiding off-target binding, thereby improving treatment reliability and reducing harmful side effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the compound structure (different substituents, stereoisomers, and derivatives of the core 3-oxabicyclo[3.3.1]nonene framework) to optimize receptor selectivity. By adjusting these chemical parameters, the compound achieves enhanced binding specificity for ERα/β receptors while maintaining minimal cross-reactivity with GPER/GPR30, resolving the contradiction between effectiveness and side effects.
2Reliability
If compounds are designed to selectively bind to ERα/β receptors, then specificity is improved, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the compound into a core structural framework (3-oxabicyclo[3.3.1]nonene) and variable substituent components (R1-R9 groups). This modular approach allows systematic optimization of specificity through substituent selection while maintaining a manageable core structure, balancing selectivity improvement with structural complexity control.
Solution Approach 2:
The patent utilizes composite material principles by combining the rigid 3-oxabicyclo[3.3.1]nonene core with flexible substituent groups that can be independently optimized. This composite structure enables precise tuning of receptor interaction properties through substituent modification, achieving high binding specificity without excessive overall molecular complexity.
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 include cancer (including but not limited to breast (particularly endocrine or anti-hormone resistant, and for the prevention/reduction of endocrine or anti-hormone resistance), reproductive and other hormone-dependent cancers, leukemia, colon cancer, prostate cancer), reproductive (genito-urological) including endometritis, prostatitis, polycystic ovarian syndrome, bladder control, hormone-related disorders, hearing disorders, cardiovascular conditions including hot flashes and profuse sweating, hypertension, stroke, obesity, osteoporosis, hematologic diseases, vascular diseases or conditions such as venous thrombosis, atherosclerosis, among numerous others and disorders of the central and peripheral nervous system, including depression, insomnia, anxiety, multiple sclerosis, neuropathy, neurodegenerative disorders (such as Parkinson's disease and Alzheimer's disease), as well as inflammatory bowel disease, Crohn's disease, coeliac (celiac) disease and related disorders of the intestine, among numerous others as described herein. A contraceptive indication to prevent or reduce the likelihood of pregnancy after intercourse is a further aspect of the present invention.