Isoxazole FXR Agonists for Intestinal Absorption and Stability
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Solution Overview
Problem
Current FXR agonists, such as GW4064, exhibit limited intestinal absorption, short terminal half-life, and UV light instability, leading to potential cell toxicity and side effects like dis-regulation in serum lipids and liver steatosis.
Innovation Solution
Development of novel isoxazole derivatives as selective FXR agonists with improved pharmacokinetic properties, including specific chemical moieties and pharmaceutical compositions to enhance bioavailability and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GW4064 is used as an FXR agonist, then FXR activation is achieved, but intestinal absorption is limited
Solution Approach 1:
The patent applies parameter changes by systematically modifying the chemical structure of GW4064 through various substitutions on the isoxazole core, phenyl ring, and side chains. These structural parameter changes result in compounds with improved intestinal absorption while maintaining FXR activation capability, as evidenced by the systematic exploration of different R1-R6 substituents in the general formula.
2Reliability
If GW4064 is used as an FXR agonist, then FXR activation is achieved, but terminal half-life is short
Solution Approach 1:
The patent employs parameter changes by introducing various substituents (halogens, alkyl groups, ester groups, nitrile) at different positions of the isoxazole and phenyl rings to modify the pharmacokinetic properties. These structural modifications aim to extend terminal half-life while preserving FXR binding affinity and activation efficacy.
3Reliability
If GW4064 is used as an FXR agonist, then FXR activation is achieved, but UV light stability is poor
Solution Approach 1:
The patent addresses UV light stability through parameter changes by replacing hydrogen atoms with more stable substituents such as halogens (Cl, F), alkyl groups, and electron-withdrawing groups (CN, COOR) on the aromatic rings. These modifications enhance the compound's resistance to photodegradation while maintaining the essential FXR agonist activity.
4Reliability
If GW4064 is used as an FXR agonist, then FXR activation is achieved, but cell toxicity increases
Solution Approach 1:
The patent applies local quality by making specific localized modifications to the molecule - introducing stable substituents at particular positions (R1-R6) that reduce toxicity at those local sites while preserving the overall FXR activation function. This localized optimization reduces cell toxicity without compromising therapeutic efficacy.
5Reliability
If GW4064 is used as an FXR agonist, then FXR activation is achieved, but serum lipid dis-regulation occurs
Solution Approach 1:
The patent uses parameter changes to modify the pharmacokinetic profile of the FXR agonist, aiming to achieve more physiological and sustained activation of FXR. By optimizing structural parameters (substituents R1-R6), the compounds seek to produce gentler, more controlled effects on serum lipid metabolism, avoiding the dis-regulation observed with GW4064.
Data Source
AI summary
The present invention relates to compounds of formula (I), to pharmaceutical compositions thereof and to their uses, in particular in the treatment and/or prevention of FXR mediated diseases.