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 (II), 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 (e.g., 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 designing GPR40 agonists with specific molecular structures (Formula I and Formula II) that modify the activation parameters of the GPR40 receptor. These compounds change the binding affinity and activation characteristics to achieve glucose-dependent insulin secretion, thereby enhancing insulin secretion while avoiding hypoglycemia through selective receptor activation only in the presence of elevated glucose levels

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The patent uses GPR40 receptor as an intermediary mechanism. The GPR40 agonists act through this specific receptor as a mediator that senses glucose levels and triggers insulin secretion only when glucose is elevated. This intermediary mechanism provides selective control, allowing insulin secretion enhancement without the direct, non-selective stimulation that causes hypoglycemia with traditional secretagogues

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

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

Engineering Contradiction:

Improveglucose-dependent insulin secretionVSAvoidtreatment complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent employs small molecule GPR40 agonists that can be administered as simple oral or injectable formulations without requiring complex delivery systems. Unlike GLP-1 drugs that often require sophisticated injection mechanisms or continuous infusion systems, these small molecules provide a simpler, more accessible treatment approach while achieving the same therapeutic goal of glucose-dependent insulin secretion

Inventive Principle:

Principle #27Cheap short-living objects (Disposable)

Solution Approach 2:

The patent extracts and isolates the key functional mechanism from the complex GLP-1 pathway by directly targeting GPR40 receptor activation. This extraction approach simplifies the treatment mechanism to a single receptor-targeted action, eliminating the need for complex enzymatic cascades and multiple protein interactions required by GLP-1 based therapies

Inventive Principle:

Principle #2Taking out (Extraction)

3Reliability

If broad-spectrum insulin sensitizers are used to treat insulin resistance, then insulin sensitivity is improved, but the safety profile is limited due to off-target effects

Engineering Contradiction:

Improveinsulin sensitivity improvementVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by designing GPR40 agonists with high receptor selectivity that act specifically on pancreatic beta cells expressing GPR40. This localized action at the target tissue level ensures insulin secretion enhancement without affecting other organ systems, thereby improving insulin sensitivity benefits while minimizing off-target effects that plague broad-spectrum insulin sensitizers

Inventive Principle:

Principle #3Local quality

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 an improved safety profile compared 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 EffectReceptor activation:

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 EffectG-protein coupled signaling:

Data Source

PatentUS9908873B2GPR40 agonists for the treatment of type II diabetes

Publication Date: 2018.03.06 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 (II) as follows:wherein R1B, R2B, R4B, WB, XB, YB, and GB, are defined herein.