Chenodeoxycholic Acid Analogues for TGR5 Modulation

Solution Overview

Problem

Current TGR5 modulators are not potent or selective enough to fully characterize the physiological and pharmacological actions of the TGR5 receptor, necessitating the development of more effective compounds for treating and preventing metabolic, inflammatory, liver, autoimmune, cardiac, kidney, and gastrointestinal diseases.

Innovation Solution

Development of chenodeoxycholic acid analogues with a substituent at the C-16 position, which act as potent and selective TGR5 modulators, including compounds with specific structural formulas that can be used in pharmaceutical compositions for administration, to modulate the TGR5 receptor effectively.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Measurement precision

If existing TGR5 modulators are used, then some TGR5 modulation activity is achieved, but the potency and selectivity are insufficient to fully characterize physiological and pharmacological actions

Engineering Contradiction:

ImproveselectivityVSAvoidpotency

Core Design Contradiction:

Measurement precisionVSReliability

Solution Approach 1:

The patent introduces specific substituents at defined positions (C-16 position with various groups R16, and C-6 position with R4) on the chenodeoxycholic acid core structure. This local modification approach enhances both potency and selectivity by optimizing interactions with specific amino acid residues in the TGR5 binding pocket while maintaining structural recognition

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent systematically varies chemical parameters including the type of substituent at C-16 (hydroxy, halogen, alkoxy, amino, etc.), the substituent at C-6 (alkyl groups), and the stereochemistry (α/β configurations) to optimize TGR5 modulation. These parameter changes enable fine-tuning of both potency and selectivity characteristics

Inventive Principle:

Principle #35Parameter changes

2Reliability

If current TGR5 modulators are used, then some therapeutic effect is observed, but they are not potent or selective enough for comprehensive disease treatment

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidreceptor selectivity

Core Design Contradiction:

ReliabilityVSMeasurement precision

Solution Approach 1:

The patent introduces specific substituents at defined positions (C-16 position with various groups R16, and C-6 position with R4) on the chenodeoxycholic acid core structure. This local modification approach enhances both potency and selectivity by optimizing interactions with specific amino acid residues in the TGR5 binding pocket while maintaining structural recognition

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent systematically varies chemical parameters including the type of substituent at C-16 (hydroxy, halogen, alkoxy, amino, etc.), the substituent at C-6 (alkyl groups), and the stereochemistry (α/β configurations) to optimize TGR5 modulation. These parameter changes enable fine-tuning of both potency and selectivity characteristics

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentEP3150620B1TGR5 modulators and methods of use thereof

Publication Date: 2020.01.08 INTERCEPT PHARMACEUTICALS INC

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Figure 2A~2B
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AI summary

The invention relates to compounds of Formula (A): (A) or a salt, solvate, hydrate, or amino acid conjugate thereof. The compounds of formula A are TGR5 modulators useful for the prevention and treatment of disease.