FXR Modulators Formula I Metabolic Disease Treatment
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Solution Overview
Problem
Current FXR activators for treating diseases associated with farnesoid X receptor (FXR) have limitations due to toxicities and adverse effects, necessitating the development of novel and potent small molecule FXR modulators.
Innovation Solution
A compound of Formula I, or its pharmaceutically acceptable salts, hydrates, solvates, prodrugs, stereoisomers, or tautomers, is administered to patients to modulate FXR activity, treat various diseases, including liver and intestinal disorders, autoimmune diseases, and cancer, by activating FXR and regulating metabolic and inflammatory pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If known FXR activators are used to treat metabolic and inflammatory diseases, then therapeutic effects are achieved, but toxicities and adverse effects occur
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of FXR activators through systematic variations in molecular parameters (substituents R1-R6, ring systems, linkers L1-L2) to optimize the balance between therapeutic efficacy and safety profile. This involves changing physical and chemical parameters of the compound to achieve desired pharmacological effects while minimizing toxicities.
Solution Approach 2:
The patent applies local quality by introducing specific functional groups and substituents at particular positions in the molecular structure (e.g., R1 and R2 on the aryl/heteroaryl ring, R3 on the piperidine/piperazine ring) to achieve localized effects on FXR activation and metabolic pathways, thereby improving therapeutic index through site-specific molecular modifications.
2Reliability
If FXR activation is enhanced to improve treatment of liver and intestinal diseases, then disease progression is slowed, but adverse effects increase
Solution Approach 1:
The patent applies partial or excessive action by designing FXR modulators that achieve sufficient activation of FXR to produce therapeutic effects without excessive activation that would lead to adverse effects. This is accomplished through careful optimization of molecular structure to achieve the right degree of receptor activation.
Solution Approach 2:
The patent converts the potential harm of FXR overactivation into benefit by designing compounds that selectively activate FXR in specific tissues (liver, intestine) while avoiding systemic side effects, thereby transforming what could be harmful excessive activation into beneficial localized therapeutic action.
3Adaptability or versatility
If novel FXR modulators are developed to overcome limitations of current treatments, then therapeutic options are expanded, but development complexity increases
Solution Approach 1:
The patent applies universality by designing a core molecular scaffold (Formula I) that can serve multiple therapeutic indications including metabolic diseases, inflammatory conditions, and liver diseases. The versatile structure can be adapted to treat various FXR-related disorders through modification of substituents while maintaining the core FXR activation mechanism.
Solution Approach 2:
The patent applies segmentation by dividing the molecular structure into distinct functional segments (core scaffold, substituents R1-R6, linkers L1-L2) that can be independently optimized. This modular approach allows systematic exploration of structure-activity relationships while managing the complexity of novel compound development.
Data Source
AI summary
The invention relates to activators of FXR useful in the treatment of autoimmune disorders, liver disease, intestinal disease, kidney disease, cancer, and other diseases in which FXR plays a role, having the Formula (I): wherein L1, A, X1, X2, Y1, Y2, Y3, Y4, R1, R2, and R3 are described herein.