Selective FXR Modulator Compounds With Minimal TGR5 Activation
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Solution Overview
Problem
Existing therapeutic compounds that modulate the farnesoid X receptor (FXR) face challenges such as non-selectivity for other nuclear receptors, undesirable pharmacokinetic profiles, and safety issues like toxicity and drug-drug interactions, necessitating the development of selective FXR modulators that minimize activation of the bile acid GPCR TGR5.
Innovation Solution
Development of compounds of formula I, including pharmaceutically acceptable salts, solvates, and amino acid conjugates, which selectively modulate FXR with minimal activation of TGR5, addressing the need for safer and more effective FXR-targeted therapies.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If natural bile acids and bile acid derivatives are used as FXR modulators, then FXR-mediated diseases and conditions can be regulated, but selectivity against other nuclear receptors and TGR5 is compromised leading to increased side effects
Solution Approach 1:
The patent applies local quality by introducing specific substituent groups at defined positions (R1-R10) on the bile acid core structure. Each substituent is carefully selected to enhance FXR binding affinity while reducing interactions with other nuclear receptors and TGR5, thereby achieving selective modulation at the molecular level.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters such as substituent types (halogen, alkyl, alkoxy, oxo groups), their positions on the steroid core, and stereochemistry. These parameter modifications transform the general FXR modulator into a selective agent with improved safety profile.
2Reliability
If existing FXR modulators are used for therapy, then FXR-mediated diseases can be treated, but pharmacokinetic profiles are unsuitable and safety issues such as toxicity and drug-drug interactions arise
Solution Approach 1:
The patent extracts the problematic properties of existing FXR modulators by removing or modifying the portions of the molecular structure responsible for non-selective binding and adverse pharmacokinetic behavior, while retaining the core FXR-binding pharmacophore.
Solution Approach 2:
The patent creates composite molecular structures by combining the bile acid core with specific substituent patterns that collectively provide both FXR selectivity and improved pharmacokinetic properties, reducing toxicity and drug-drug interactions.
3Adaptability or versatility
If non-selective therapeutic compounds are used to modulate FXR, then FXR-mediated diseases can be addressed, but activation of other nuclear receptors and TGR5 increases risk of side effects
Solution Approach 1:
The patent segments the receptor binding interaction into distinct molecular components, where specific substituents on the bile acid core are responsible for FXR selectivity while minimizing interactions with other nuclear receptors and TGR5, achieving targeted modulation without off-target effects.
Data Source
AI summary
The present application provides a compound of formula I:or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, wherein R1-R10, m, n, p, and are as described herein. The present invention relates generally to F modulators and to methods of making and using said compounds.