Isoxazole Derivatives as Selective FXR Agonists
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Solution Overview
Problem
There is a need for effective FXR modulators for the treatment and prevention of various diseases, as existing small molecule FXR modulators have limitations in modulating human or mouse FXR receptors and do not effectively address FXR-mediated conditions such as cardiovascular diseases, liver diseases, and metabolic disorders.
Innovation Solution
Development of isoxazole derivatives represented by Formula I, which act as FXR agonists, including specific compounds and pharmaceutical compositions for administering therapeutically effective amounts to treat or prevent FXR-mediated diseases, with these compounds being designed to selectively activate FXR over TGR5 activators.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing small molecule FXR modulators are used, then FXR modulation is attempted, but they fail to effectively modulate human or mouse FXR receptors
Solution Approach 1:
The patent modifies molecular parameters of FXR modulators by incorporating specific structural features including isoxazole rings, heteroaryl groups, and defined substituent patterns (R1-R6 groups) to enhance binding affinity and selectivity for human and mouse FXR receptors, resolving the species specificity issue
2Reliability
If FXR modulators are developed for treating cardiovascular diseases, liver diseases, and metabolic disorders, then therapeutic benefits are achieved, but selectivity between FXR and TGR5 activation must be maintained
Solution Approach 1:
The patent introduces specific local structural features in the molecule (isoxazole core with particular substituent configurations at R1-R6 positions) that create selective interaction with FXR receptor binding site, distinguishing it from TGR5 activation while maintaining therapeutic effectiveness for cardiovascular, liver, and metabolic diseases
Data Source
AI summary
The present invention provides compounds of Formula I,pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated as FXR modulators. Specifically, the present invention relates to isoxazole derivatives useful as agonists for FXR, and methods for their preparation and use.