Pyrazinone Derivatives Glucose-Dependent Insulin Secretion

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current treatments for type 2 diabetes, such as sulfonylureas, induce insulin secretion independently of glucose levels, leading to side effects like hypoglycemia and beta cell exhaustion, while GLP-1 analogs are peptides requiring parenteral administration, lacking the benefits of an oral small molecule.

Innovation Solution

Pyrazinone derivatives of formula (I), which stimulate insulin secretion specifically in response to glucose, potentially preserving or increasing beta cell mass, thereby addressing the defects in insulin secretion and resistance in type 2 diabetes.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If sulfonylureas are used to induce insulin secretion, then insulin secretion is stimulated, but hypoglycemia and beta cell exhaustion occur

Engineering Contradiction:

Improveinsulin secretion stimulationVSAvoidhyperinsulinemia leading to hypoglycemia and beta cell exhaustion

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The pyrazinone derivatives exhibit glucose-dependent insulin secretion, where the insulin release is automatically regulated by the plasma glucose level. High glucose levels stimulate insulin secretion, while low glucose levels suppress it, creating a feedback mechanism that prevents hypoglycemia and beta cell exhaustion.

Inventive Principle:

Principle #23Feedback

Solution Approach 2:

The invention changes the parameter of glucose dependency in insulin secretion. Unlike sulfonylureas that stimulate insulin secretion independently of glucose levels, the pyrazinone derivatives only stimulate insulin secretion when glucose levels are high, thereby adapting the insulin release to physiological needs.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If GLP-1 analogs are used to restore normal insulin release profile, then glucose-induced insulin secretion is improved, but parenteral administration is required

Engineering Contradiction:

Improveglucose-induced insulin secretionVSAvoidadministration route

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The invention replaces the need for parenteral administration (injection) with oral administration. The pyrazinone derivatives are small molecule compounds that can be absorbed through the gastrointestinal tract, eliminating the mechanical complexity of injection systems while maintaining the beneficial glucose-dependent insulin secretion profile.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

Solution Approach 2:

The invention changes the administration route parameter from parenteral to oral. This transformation is achieved by designing small molecule compounds that are suitable for oral bioavailability, thereby simplifying patient compliance and eliminating the need for medical personnel involvement in administration.

Inventive Principle:

Principle #35Parameter changes

3Reliability

If sulfonylureas are used to stimulate insulin secretion, then insulin release is increased, but beta cell mass is not preserved

Engineering Contradiction:

Improveinsulin secretionVSAvoidbeta cell mass

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The glucose-dependent mechanism acts as a protective feedback system that prevents chronic hyperinsulinemia. By automatically reducing insulin secretion when glucose levels are normal or low, the system preserves beta cell mass while still providing adequate insulin secretion during hyperglycemic states.

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS9102632B2Pyrazinone derivatives as insulin secretion stimulators, methods for obtaining them and use thereof for the treatment of diabetes

Publication Date: 2015.08.11 MERCK PATENT GMBH

AI summary

The treatment of diabetes and associated pathologies is achieved by administering the pyrazinone compounds of formula (I)