Alkene Spirocyclic FXR Modulators for Fibrosis
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Solution Overview
Problem
Current treatments for diseases associated with dysregulated bile acids, such as nonalcoholic steatohepatitis (NASH) and primary biliary cirrhosis, lack effective pharmacological agents that can modulate farnesoid X receptor (FXR) activity to address pathological fibrosis and metabolic disorders.
Innovation Solution
Development of novel compounds represented by Formulas (I) and (II), which are FXR modulators, including stereoisomers, tautomers, pharmaceutically acceptable salts, and solvates, for use in pharmaceutical compositions to treat conditions like NASH, NAFLD, primary sclerosing cholangitis, and primary biliary cirrhosis, either alone or in combination with other therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional treatments are used for diseases associated with dysregulated bile acids, then existing therapeutic options are limited, but effective pharmacological agents that can modulate FXR activity are unavailable
Solution Approach 1:
The patent segments the therapeutic approach by developing a series of related but distinct FXR modulator compounds with different structural features (Formula I and Formula II compounds), allowing selection of specific compounds based on disease indication and patient needs, thereby providing versatile therapeutic options while maintaining reliable FXR modulation
Solution Approach 2:
The patent applies parameter changes by systematically varying chemical parameters (substituents R1-R10, ring structures, stereochemistry) of the FXR modulator compounds to optimize therapeutic effectiveness for different bile acid-related diseases, creating a library of compounds with tailored pharmacological properties
2Reliability
If FXR agonists are used to regulate bile acid homeostasis, then beneficial effects on bile acid concentrations are achieved, but comprehensive modulation of fibrosis and metabolic pathways requires additional therapeutic mechanisms
Solution Approach 1:
The FXR modulator compounds of the patent exhibit multi-functionality by simultaneously regulating bile acid homeostasis, modulating fibrosis pathways, and influencing metabolic pathways through FXR activation, allowing a single compound to address multiple aspects of bile acid-related diseases including NASH, PBC, and cholestasis
Solution Approach 2:
The patent employs composite molecular structures combining various structural elements (aromatic rings, heterocyclic groups, substituent patterns) to create FXR modulators that can simultaneously interact with multiple target pathways, achieving comprehensive modulation of bile acid, fibrosis, and metabolic pathways
Data Source
AI summary
The present invention provides compounds of Formula (I), or stereoisomers, tautomers, or pharmaceutically acceptable salts or solvates thereof, wherein all the variables are as defined herein. These compounds modulate the activity of farnesoid X receptor (FXR), for example, as agonists. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.