Biaryl Derivative DGAT2 Inhibitors for Liver-Selective Triglyceride Reduction

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Solution Overview

Problem

Current therapies for metabolic diseases such as obesity, diabetes, and cardiovascular diseases associated with excessive triglyceride accumulation lack effective inhibitors for diacylglycerol acyltransferase 2 (DGAT2), which are crucial for triglyceride biosynthesis.

Innovation Solution

Development of a biaryl derivative compound represented by Formula (1) that exhibits inhibitory activity against DGAT2, along with its pharmaceutically acceptable salts and isomers, which can be formulated into pharmaceutical compositions for treating metabolic disorders.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional therapies are used for metabolic diseases, then general treatment is provided, but effective inhibition of DGAT2 is not achieved

Engineering Contradiction:

ImproveDGAT2 inhibition efficacyVSAvoidtherapeutic effectiveness

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies parameter changes by modifying the chemical structure parameters of the compound to achieve selective DGAT2 inhibition. The biaryl derivative with specific structural parameters (Formula 1 with defined R1-R6 substituents) provides optimal binding affinity to DGAT2, resolving the contradiction between reliable inhibition and therapeutic effectiveness.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent applies local quality by designing the inhibitor with specific local structural features that target DGAT2's active site. The biaryl core with particular substituent patterns creates localized interactions with DGAT2, enabling selective inhibition while maintaining overall therapeutic versatility.

Inventive Principle:

Principle #3Local quality

2Reliability

If DGAT2 inhibition is achieved, then triglyceride synthesis is reduced, but liver selectivity and exposure need to be enhanced

Engineering Contradiction:

Improvetriglyceride synthesis reductionVSAvoidliver exposure concentration

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent modifies physicochemical parameters of the biaryl derivative, specifically optimizing lipophilicity (logP) and molecular size to enhance liver uptake. The balanced structural parameters enable the compound to achieve both effective DGAT2 inhibition and sufficient liver exposure concentrations for therapeutic effect.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If biaryl derivative compound is developed, then DGAT2 inhibitory activity is achieved, but pharmaceutical formulation and administration convenience need improvement

Engineering Contradiction:

ImproveDGAT2 inhibitory activityVSAvoidpharmaceutical administration convenience

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent optimizes formulation parameters including pH, solubility enhancers, and excipient selection to improve the biaryl derivative's pharmaceutical properties. These parameter adjustments maintain DGAT2 inhibitory activity while enhancing administration convenience through improved solubility and stability.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS12459915B2Biaryl derivative useful as diacylglycerol acyltransferase 2 inhibitor, and use thereof

Publication Date: 2025.11.04 LG CHEM LTD

AI summary

The present invention relates to a biaryl derivative compound, which exhibits the activity of a diacylglycerol acyltransferase 2 (DGAT2) inhibitor and is represented by chemical formula (1), a pharmaceutical composition comprising same as an active ingredient, and a use thereof.