Selective FXR Agonists Modulating Bile Acid Metabolism
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Solution Overview
Problem
There is a need for novel compounds that act as specific agonists for the nuclear hormone farnesoid X receptor (FXR) to treat metabolic and chronic liver diseases, with challenges including selectivity issues, unsuitable pharmacokinetic profiles, toxicity, and undesirable drug-drug interactions.
Innovation Solution
Development of compounds that are potent FXR agonists with specific activation profiles, avoiding activity on other nuclear receptors and the bile acid GPCR TGR5, and possessing favorable pharmacokinetic properties, such as Compound 100, which is synthesized through specific chemical processes to ensure safety and efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If bile acids are used as FXR ligands, then FXR activation is achieved, but selectivity issues arise with other nuclear receptors and TGR5
Solution Approach 1:
The patent applies local quality by introducing specific substituent patterns at defined positions on the steroid core structure. The compound features a carbonyl group at position 11 and specific hydroxyl group configurations that create localized chemical properties enabling selective binding to FXR while avoiding other nuclear receptors and TGR5.
Solution Approach 2:
The patent employs parameter changes by systematically varying substituent groups (R1-R6) at different positions on the steroid nucleus. Specific parameter combinations such as R2=hydroxyl, R3=hydroxyl, R4=hydroxyl, R5=hydroxyl, and R6=hydroxyl create compounds with optimized FXR selectivity and pharmacokinetic properties.
2Reliability
If FXR agonists are developed to treat metabolic diseases, then therapeutic efficacy is improved, but toxicity and drug-drug interactions increase
Solution Approach 1:
The patent extracts the essential pharmacophore elements required for FXR activation while removing structural features that cause toxicity and off-target effects. The simplified steroid core with specific functional groups maintains therapeutic efficacy while eliminating harmful properties associated with bile acid-based FXR ligands.
Solution Approach 2:
The patent introduces specific functional groups as intermediaries that mediate selective interaction with FXR. The carbonyl group at position 11 and hydroxyl groups at specific positions act as intermediary elements that facilitate high-affinity binding to FXR while preventing interactions with other nuclear receptors and metabolic enzymes.
3Reliability
If compounds are designed for high FXR potency, then receptor activation is enhanced, but pharmacokinetic properties deteriorate
Solution Approach 1:
The patent applies parameter changes by optimizing the balance between hydrophobic and hydrophilic regions of the molecule. The specific configuration of hydroxyl groups provides appropriate solubility and metabolic stability, while the steroid core maintains high-affinity binding to FXR, achieving both potent receptor activation and favorable pharmacokinetic properties.
Data Source
AI summary
The present invention provides a compound of formula (I): or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1, R2, R3, R4, R5, and R6 are as described herein. The present invention relates generally to selective FXR agonists and to methods of making and using them.