GLP-1 Receptor Agonist Compounds for Oral Diabetes Treatment
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Solution Overview
Problem
Current diabetes treatments using GLP-1 analogs have limitations due to short action time and require injection administration, and there is a need for a therapeutic agent that does not cause QT prolongation, which can lead to cardiotoxicity.
Innovation Solution
Development of novel GLP-1 receptor agonist compounds represented by specific chemical formulas, which can be administered orally and have a longer half-life, along with pharmaceutical compositions for treating metabolic diseases, including diabetes, while ensuring cardiovascular safety by minimizing hERG channel inhibition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If GLP-1 analogs are used to extend half-life, then duration of action is improved, but ease of operation deteriorates due to injection requirement
Solution Approach 1:
The patent develops small molecule GLP-1R agonists with altered chemical parameters (molecular structure, lipophilicity, metabolic stability) that enable oral absorption while maintaining extended half-life through resistance to DPP-4 enzymatic degradation, thus resolving the contradiction between duration of action and administration convenience
2Reliability
If strict blood sugar control is implemented, then reliability of preventing complications is improved, but object-generated harmful factors worsen due to hypoglycemia risk
Solution Approach 1:
The GLP-1R agonist compounds act on glucose-dependent insulin secretion mechanisms, where insulin release is stimulated only when blood glucose levels are elevated, providing automatic feedback control that prevents hypoglycemia while maintaining effective glucose control and preventing diabetic complications
3Reliability
If GLP-1 receptor agonism is achieved, then effectiveness in lowering blood sugar is improved, but object-generated harmful factors worsen due to QT prolongation and cardiotoxicity
Solution Approach 1:
The patent extracts and isolates the therapeutic hypoglycemic effect of GLP-1R agonism from its harmful cardiovascular side effects by developing selective small molecule agonists that target GLP-1R without activating hERG potassium channels, thus separating the beneficial metabolic action from the detrimental cardiac effect
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 exhibit excellent glucose tolerance and pharmacokinetic properties, providing a therapeutic advantage over existing treatments by being orally available and having low risk of cardiotoxicity, thus effectively managing diabetes with improved patient convenience and safety.
Implementation Method 1
GLP-1 increases insulin secretion by acting on a receptor referred to as GLP-1R (glucagon like peptide-1 receptor). The compounds act as GLP-1 receptor agonists to stimulate insulin secretion
Implementation Method 2
therapeutic agents have been developed using a GLP-1 analog and a DPP-4 inhibitor which are resistant to an enzyme referred to as dipeptidyl peptidase IV (DPP-IV) that destroys the GLP-1 in the blood
Implementation Method 3
human ether-a-go-go related gene (hERG) is a gene that encodes a subunit of the human potassium channels responsible for the delayed rectifier potassium current (IKr), which seems to have the most influential role in determining the duration of the action potential and thus the QT interval. If the hERG channel is inhibited by drugs, the ventricular repolarization determined by the duration of the cardiac action potential is delayed, an effect that can be measured as prolongation of the QT interval on the ECG
Data Source
AI summary
Disclosed are novel compounds of Chemical Formula 1, optical isomers of the compounds, and pharmaceutically acceptable salts of the compounds or the optical isomers. The compounds, isomers, and salts exhibit excellent activity as GLP-1 receptor agonists. In particular, they, as GLP-1 receptor agonists, exhibit excellent glucose tolerance, thus having a great potential to be used as therapeutic agents for metabolic diseases. Moreover, they exhibit excellent pharmacological safety for cardiovascular systems.