Formula I GLP-1R Agonist Compounds for Oral Metabolic Treatment

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Solution Overview

Problem

There is a need for novel GLP-1R agonists that can be orally administered for treating metabolic disorders such as type-II diabetes mellitus (T2DM), obesity, and non-alcoholic steatohepatitis (NASH), as existing GLP-1R agonists are primarily administered via subcutaneous injection and oral options are limited.

Innovation Solution

Development of a series of compounds represented by Formula I, including stereoisomers and pharmaceutically acceptable salts, which can bind to and activate the GLP-1R receptor, offering an alternative to existing GLP-1R agonists.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If GLP-1R agonists are administered by subcutaneous injection, then therapeutic efficacy is achieved, but ease of operation deteriorates due to invasive administration requirements

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidease of administration

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent introduces an oral absorption enhancer as an intermediary substance that facilitates the absorption of the GLP-1R agonist through the gastrointestinal tract. This mediator enables oral administration by temporarily altering the permeability of the intestinal barrier, allowing the peptide drug to pass through without degradation while maintaining therapeutic efficacy.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs parameter changes by modifying the physical and chemical environment in the gastrointestinal tract through the use of absorption enhancers. These agents temporarily change the permeability parameters of the intestinal epithelium, enabling oral absorption of the peptide drug. The formulation also addresses stability parameters by protecting the drug from enzymatic degradation in the GI tract.

Inventive Principle:

Principle #35Parameter changes

2Ease of operation

If oral GLP-1R agonists are developed, then ease of operation improves, but reliability deteriorates due to limited clinical options and absorption challenges

Engineering Contradiction:

Improveease of administrationVSAvoidtherapeutic efficacy

Core Design Contradiction:

Ease of operationVSReliability

Solution Approach 1:

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent employs transient, short-acting absorption enhancers that are designed to be temporary and disposable in function. These enhancers work briefly to facilitate drug absorption and then are eliminated, avoiding long-term side effects and allowing for simple oral dosing without requiring sustained complex delivery systems.

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

3Duration of action of moving object

If GLP-1R agonists are designed for long action, then duration of action improves, but device complexity increases due to formulation requirements

Engineering Contradiction:

Improveduration of actionVSAvoidformulation complexity

Core Design Contradiction:

Duration of action of moving objectVSDevice complexity

Solution Approach 1:

The patent achieves continuous useful action by formulating the GLP-1R agonist with absorption enhancers that enable sustained release and continuous absorption in the gastrointestinal tract. This continuous delivery mechanism maintains therapeutic drug levels over extended periods, providing long-acting effects similar to injectable formulations but through oral administration.

Inventive Principle:

Principle #20Continuity of useful action

Solution Approach 2:

The patent employs composite materials by combining the GLP-1R agonist with oral absorption enhancers and other formulation components in a single oral dosage form. This composite formulation integrates multiple functions (drug delivery, absorption enhancement, stability protection) into one system, achieving long-acting effects without requiring complex multi-component delivery devices.

Inventive Principle:

Principle #40Composite materials

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The compounds provide a potential oral treatment option for metabolic disorders by enhancing insulin secretion and inhibiting glucagon release, addressing the limitations of current GLP-1R agonists.

Implementation Method 1

the compound provided herein has a structure represented by Formula I... which can bind to and activate the Glucagon-Like Peptide-1 Receptor (GLP-1R)

Methodology Applied

Scientific EffectReceptor binding and activation:

Implementation Method 2

The binding of GLP-1 to GLP-1R activates the heterotrimeric G proteins and subsequently enhances the activity of adenylate cyclase, which results in an increased level of cyclic adenosine monophosphate (cAMP) in the cells

Methodology Applied

Scientific EffectG protein-coupled receptor signaling:

Data Source

PatentUS12419874B2GLP-1R agonist compound and use thereof

Publication Date: 2025.09.23 YAOPHARMA CO LTD

AI summary

The present disclosure relates to a GLP-1R agonist compound and use thereof, and specifically provides a compound represented by Formula I, or an isotope-labelled compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, and use thereof as a medicament. The compound exhibits excellent agonistic effects and pharmacodynamic properties on GLP-1R and, as a modulator, is useful for manufacturing a medicament for the treatment, amelioration, or prevention of metabolic diseases and related diseases, thus having broad application prospects.