Heterocyclic IC-GPCR2 Agonists for Glucose-Dependent Insulin Secretion

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Solution Overview

Problem

Current treatments for diabetes, particularly Type II diabetes, lack effective oral medications that stimulate insulin secretion in a glucose-dependent manner, leading to challenges in managing blood glucose levels and insulin resistance.

Innovation Solution

Development of novel agonists targeting the IC-GPCR2 receptor, which raise intracellular cAMP levels to enhance glucose-dependent insulin secretion, providing a potential oral treatment for Type II diabetes and offering diagnostic benefits for pancreatic islet-related diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If conventional treatments (metformin, TZDs, sulphonylureas) are used to control blood glucose levels, then blood glucose control is improved, but hypoglycemia risk increases and insulin resistance remains unaddressed

Engineering Contradiction:

Improveblood glucose controlVSAvoidhypoglycemia risk

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent changes the mechanism of action from direct insulin secretion stimulation (sulphonylureas) or insulin sensitivity improvement (metformin, TZDs) to cAMP pathway activation via IC-GPCR2 receptor agonism. This parameter change in the therapeutic approach enables glucose-dependent insulin secretion that mimics physiological responses, improving blood glucose control while avoiding hypoglycemia through the glucose-sensing mechanism of beta cells.

Inventive Principle:

Principle #35Parameter changes

2Productivity

If sulphonylureas are used to stimulate insulin secretion, then insulin release is improved, but hypoglycemia occurs due to glucose-independent secretion

Engineering Contradiction:

Improveinsulin secretionVSAvoidhypoglycemia

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces a feedback mechanism where IC-GPCR2 agonists activate cAMP production in beta cells, which then respond to glucose levels to regulate insulin secretion. The cAMP pathway acts as an amplifying feedback loop that enhances physiological insulin secretion in response to glucose, rather than forcing secretion independent of glucose status. This feedback-based approach maintains insulin secretion productivity while preventing hypoglycemia.

Inventive Principle:

Principle #23Feedback

3Reliability

If exanatide is used to stimulate insulin secretion, then glucose-dependent insulin release is improved, but oral availability is lost requiring injection

Engineering Contradiction:

Improveglucose-dependent insulin secretionVSAvoidadministration route

Core Design Contradiction:

ReliabilityVSEase of operation

Solution Approach 1:

The patent substitutes the peptide-based mechanism (exanatide requiring injection) with a small molecule organic compound mechanism that can be orally administered. The heterocyclic compounds of the patent activate the same IC-GPCR2 receptor and cAMP pathway as exanatide but with oral bioavailability, replacing the mechanical injection requirement with oral administration capability while maintaining glucose-dependent insulin secretion reliability.

Inventive Principle:

Principle #28Mechanics substitution (Replace mechanical system)

4Productivity

If DPP-IV inhibitors (Januvia) are used to increase incretin hormones, then insulin secretion is improved, but tissue levels of other hormones are influenced with unknown long-term consequences

Engineering Contradiction:

Improveinsulin secretionVSAvoidselectivity of hormonal effect

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies local quality by designing compounds that specifically target IC-GPCR2 receptors in pancreatic beta cells, achieving localized action at the intended site. The heterocyclic compounds demonstrate selectivity for beta cell IC-GPCR2 receptors, producing insulin secretion effects without broadly influencing other hormone systems. This localized, selective mechanism improves insulin secretion productivity while maintaining hormonal system reliability and predictability.

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 IC-GPCR2 agonists effectively increase insulin secretion and lower blood glucose levels in a glucose-dependent manner, offering a promising oral therapy for Type II diabetes and aiding in the diagnosis of pancreatic islet-related diseases.

Implementation Method 1

agonists of another G-protein coupled receptor (GPCR), IC-GPCR2 is useful in the treatment of diabetes. IC-GPCR2 can also raise intracellular cAMP levels

Methodology Applied

Scientific EffectG-protein coupled receptor signaling:

Data Source

PatentUS9925189B2Heterocyclic receptor agonists for the treatment of diabetes and metabolic disorders

Publication Date: 2018.03.27 CYMABAY THERAPEUTICS INC

AI summary

Compounds and methods are provided for the treatment of, inter alia, Type II diabetes and other diseases associated with poor glycemic control. The compounds of the invention are orally active.