Heterocyclic FXR Modulators Selective Binding
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Solution Overview
Problem
Current treatments for FXR-mediated disorders such as liver disease, hyperlipidemia, and obesity lack effective modulators that can selectively target FXR without causing off-target effects, limiting their therapeutic efficacy.
Innovation Solution
Development of novel compounds, specifically stereoisomers and salts thereof, that modulate FXR by binding to the receptor, thereby treating FXR-mediated disorders such as liver disease, hyperlipidemia, obesity, and other conditions by selectively targeting FXR over other receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for FXR-mediated disorders, then they can address general symptoms, but they cause off-target effects and lack selective targeting of FXR
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (Formula I) that target only the FXR receptor. The molecular structure includes specific substituents (R1-R6, W, X, Y, Z) that are locally optimized to bind selectively to FXR's ligand-binding domain, ensuring that the therapeutic effect is concentrated at the target site without affecting other receptors.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the compound structure (different substituents, stereochemistry, and molecular weight) to optimize FXR selectivity. By adjusting these chemical parameters, the compounds achieve high affinity for FXR while maintaining selectivity against other nuclear receptors, thereby reducing off-target effects.
2Reliability
If novel heterocyclic compounds are developed to selectively target FXR, then selectivity and therapeutic efficacy are improved, but compound complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the complex heterocyclic compound into distinct functional modules represented by substituents R1-R6, W, X, Y, and Z in Formula I. Each substituent represents a separate functional element that can be independently optimized and synthesized, allowing for systematic development of analogs while managing structural complexity.
Solution Approach 2:
The patent employs universality by designing a core heterocyclic structure (Formula I) that serves multiple functions: it provides the necessary affinity for FXR binding, enables selective targeting through specific substituents, and allows for metabolic stability. This universal scaffold can be adapted to create multiple derivatives with different pharmacokinetic properties while maintaining the core therapeutic mechanism.
Data Source
AI summary
The present technology is directed to compounds of formula (I), compositions, and methods related to modulation of FXR. In particular, the present compounds and compositions may be used to treat FXR-mediated disorders and conditions, including, e.g., liver disease, hyperlipidemia, hypercholesteremia, obesity, metabolic syndrome, cardiovascular disease, gastrointestinal disease, and atherosclerosis, and renal disease.