GPR40 Agonists for Glucose-Dependent Insulin Secretion

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Solution Overview

Problem

Current treatments for Type 2 diabetes and related disorders, such as obesity and metabolic syndrome, often come with risks of hypoglycemia and limited safety profiles due to non-glucose dependent insulin secretion stimulation.

Innovation Solution

Development of GPR40 agonists, specifically compounds of Formula (I), which selectively activate the GPR40 receptor to enhance glucose-dependent insulin secretion, thereby treating Type 2 diabetes and related disorders with a safer and more targeted approach.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If insulin secretagogues (sulfonylureas, glinides) are used to stimulate insulin secretion, then insulin secretion is enhanced, but the risk of hypoglycemia increases due to non-glucose dependent secretion

Engineering Contradiction:

Improveinsulin secretion enhancementVSAvoidhypoglycemia risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies parameter changes by modifying the dependency condition of insulin secretion from non-glucose dependent to glucose dependent. The GPR40 agonist compounds are designed to respond to glucose levels, automatically adjusting insulin secretion based on glucose concentration - secreting insulin when glucose is elevated and withholding when glucose is normal, thereby eliminating hypoglycemia risk while maintaining therapeutic efficacy

Inventive Principle:

Principle #35Parameter changes

2Reliability

If GLP-1 based drugs are used to stimulate insulin secretion, then insulin secretion is enhanced in a glucose-dependent manner, but the device complexity and treatment cost increase

Engineering Contradiction:

Improveglucose-dependent insulin secretionVSAvoidtreatment mechanism complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent replaces the complex enzymatic mechanism of GLP-1 (which requires dipeptidyl-peptidase 4 inhibition or exogenous GLP-1 administration) with a direct receptor agonist approach. The GPR40 agonist compounds directly activate the GPR40 receptor without requiring enzymatic conversion or degradation inhibition, simplifying the therapeutic mechanism while maintaining glucose-dependent insulin secretion efficacy

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

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 GPR40 agonists provide a therapeutic benefit for Type 2 diabetes and related conditions by stimulating insulin secretion only in the presence of elevated glucose levels, minimizing the risk of hypoglycemia and offering a safer alternative to existing treatments.

Implementation Method 1

GPR40, also known as free fatty acid receptor 1 (FFAR1), is one of a family of G-protein coupled receptors that, through receptor deorphanization studies, was shown to be endogenously activated by medium- to long-chain saturated and unsaturated fatty acids

Methodology Applied

Scientific EffectG-protein coupled receptor signaling:

Implementation Method 2

Operating primarily through Gαq/11 signaling, GPR40 activation of the beta cell leads to an increase in intracellular calcium levels, which in the presence of glucose, ultimately results in augmented insulin secretion

Methodology Applied

Scientific EffectCalcium signaling:

Data Source

PatentUS9920040B2GPR40 agonists for the treatment of type II diabetes

Publication Date: 2018.03.20 JANSSEN PHARMA NV

AI summary

Disclosed are compounds, compositions and methods for treating of disorders that are affected by the modulation of the GPR40 receptor. Such compounds are represented by Formula (I), as follows:wherein R1, R2, R4, W, X, Y, and G, are defined herein.