Dicarba-closo-dodecaborane Compounds for Selective ERβ Agonism
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Solution Overview
Problem
Developing compounds with estrogen receptor (ER) subtype specificity is challenging due to the similarity in structure and amino acid sequence of ERα and ERβ ligand binding domains, which limits the development of non-selective estrogen modulators for treating ERβ-related diseases without adverse effects on ERα.
Innovation Solution
The development of compounds comprising dicarba-closo-dodecaborane clusters with specific substitutions that selectively target ERβ, offering agonist activity without undesired effects on ERα, thereby providing therapeutic options for ERβ-related diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective estrogen modulators are used to treat ERβ-related diseases, then therapeutic effects on ERβ are achieved, but adverse effects on ERα occur
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular features (dicarba-closo-dodecaborane core with particular substituents at positions 2 and 7) that create selective affinity for ERβ over ERα. The specific substitution pattern (R1, R2, R3, R4, R5, R6 independently selected from defined groups) enables the molecule to interact preferentially with ERβ's ligand binding domain while minimizing interaction with ERα, thus achieving localized selective action at the target receptor subtype.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters of the carborane compound structure (different substituent groups R1-R6, different carborane cluster configurations) to optimize ERβ selectivity. By adjusting these chemical parameters and evaluating their impact on receptor binding affinity and selectivity ratios (ERβ/ERα), the invention identifies structural parameters that maximize therapeutic selectivity while minimizing off-target effects.
2Adaptability or versatility
If compounds with ER subtype specificity are developed, then selective treatment of ERβ-related diseases is enabled, but the complexity of drug development increases due to similarity in ligand binding domains
Solution Approach 1:
The patent applies segmentation by dividing the complex problem of achieving ERβ selectivity into manageable structural components: the core dicarba-closo-dodecaborane cluster and six independently optimizable substituent positions (R1-R6). This segmentation allows systematic exploration of structure-activity relationships by varying one substituent at a time while holding others constant, thereby reducing the overall complexity of the drug development process despite the need for high selectivity.
Solution Approach 2:
The patent uses the dicarba-closo-dodecaborane cluster as an intermediary structure that mediates selective interaction between the drug molecule and ERβ. This unique carborane core serves as a structural mediator that, when combined with specific substituents, creates a molecular interface preferentially recognized by ERβ's ligand binding domain, thereby enabling selective targeting despite the overall similarity between ERα and ERβ structures.
Data Source
AI summary
Disclosed herein are compounds comprising dicarba-closo-dodecaborane. The compounds can be, for example, estrogen receptor beta (ERβ) agonists. In some examples, the compounds can be selective ERβ agonists. Also provided herein are methods of treating, preventing, or ameliorating cancer in a subject, suppressing tumor growth in a subject, treating an inflammatory disease in a subject, treating a neurodegenerative disease in a subject, treating a psychotropic disorder in a subject, or a combination thereof, by administering to a subject a therapeutically effective amount of one or more of the compounds or compositions described herein, or a pharmaceutically acceptable salt thereof.