Substituted Amide FXR Modulators for Stability and Toxicity Trade-offs

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Solution Overview

Problem

Current FXR modulators face challenges in achieving optimal stability, bioavailability, therapeutic index, and toxicity values, which are crucial for their effectiveness as pharmaceuticals in treating diseases associated with farnesoid X receptor activity.

Innovation Solution

Development of substituted amide compounds of Formula (I) and their pharmaceutical compositions, which serve as FXR modulators, offering improved stability, bioavailability, and therapeutic profiles compared to existing FXR modulators.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If current FXR modulators are used, then they can treat diseases associated with FXR activity, but they face challenges in achieving optimal stability, bioavailability, therapeutic index, and toxicity values

Engineering Contradiction:

ImprovestabilityVSAvoidtoxicity

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies parameter changes by systematically modifying chemical parameters of FXR modulators, including substituting hydrogen atoms with fluorine, chlorine, or other groups at specific positions on the molecular structure. These parameter changes optimize the balance between stability and toxicity by adjusting electronic properties, lipophilicity, and metabolic stability of the compounds

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent employs composite materials by combining multiple structural moieties into a single FXR modulator molecule, creating compounds with fused ring systems, heterocyclic groups, and various substituent patterns. This composite approach allows integration of pharmacophores that enhance stability while minimizing toxic effects through strategic molecular design

Inventive Principle:

Principle #40Composite materials

2Reliability

Engineering Contradiction:

ImprovestabilityVSAvoidbioavailability

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The patent modifies physicochemical parameters including molecular weight, logP values, and hydrogen bonding capacity through strategic substitution patterns. These changes optimize oral bioavailability by improving solubility and membrane permeability while maintaining metabolic stability

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent replaces metabolic labile groups with metabolically stable analogs, such as substituting C-H bonds with C-F bonds to prevent oxidative metabolism. This substitution strategy enhances both stability and bioavailability by reducing first-pass metabolism and increasing systemic exposure

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

3Adaptability or versatility

Engineering Contradiction:

Improvetherapeutic indexVSAvoidtoxicity

Core Design Contradiction:

Adaptability or versatilityVSObject-generated harmful factors

Solution Approach 1:

The patent applies local quality by introducing specific substituents at particular positions on the FXR modulator scaffold that locally enhance binding affinity and selectivity. This localized modification improves the therapeutic index by increasing potency and selectivity while minimizing off-target effects and toxicity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent converts potentially harmful metabolic liabilities into beneficial features by identifying metabolic soft spots and replacing them with metabolically stable groups. This transformation maintains or enhances efficacy while reducing toxic metabolite formation, thereby improving the therapeutic index

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Data Source

PatentUS12319676B2Substituted amide compounds useful as farnesoid X receptor modulators

Publication Date: 2025.06.03 BRISTOL MYERS SQUIBB CO

AI summary

Disclosed are compounds of Formula (I): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, when Q is: (i) halo, cyano, hydroxyl, NRxRx, C(O)OH, C(O)NH2, C1-6 alkyl substituted with zero to 6 R1a, or P(O)R1cR1c, or (ii) L R1; and A, X1, X2, X3, X4, Z1, Z2, R1, R1a, R1c, R2, R3a, R3b, Rx, L, a, b, and d are defined herein. Also disclosed are methods of using these compounds to modulate the activity of farnesoid X receptor (FXR); pharmaceutical compositions comprising these compounds; and methods of treating a disease, disorder, or condition associated with FXR dysregulation, such as pathological fibrosis, transplant rejection, cancer, osteoporosis, and inflammatory disorders, by using the compounds and pharmaceutical compositions.