GLP-1R Modulating Compounds for Oral Agonist Delivery
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Solution Overview
Problem
There is a need for compounds that act as GLP-1R agonists with desirable therapeutic properties and easy administration for the treatment of metabolic diseases such as NASH, obesity, and Type 2 diabetes, as current GLP-1R agonists like exenatide, liraglutide, and dulaglutide are predominantly administered by subcutaneous injection and have limitations in oral formulations.
Innovation Solution
Development of compounds that bind to and act as GLP-1R agonists or modulators, represented by Formula (I-A-1), which can be administered orally and have specific structural features allowing for metabolic activity and ease of administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1R agonists are administered by subcutaneous injection, then therapeutic efficacy is improved, but ease of administration deteriorates
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of GLP-1R agonists from peptides to small molecules, which fundamentally changes the pharmacokinetic parameters including oral bioavailability and metabolic stability, enabling oral administration while maintaining therapeutic efficacy
Solution Approach 2:
The patent employs composite material strategies by designing small molecule compounds with specific structural features that combine pharmacophoric elements necessary for GLP-1R binding affinity and selectivity, achieving both efficacy and oral deliverability
2Ease of operation
If oral GLP-1 agonists are developed, then ease of administration is improved, but reliability deteriorates due to limitations in oral formulations
Solution Approach 1:
The patent changes key pharmacokinetic parameters by developing small molecule agonists with enhanced metabolic stability and oral bioavailability, overcoming the typical limitations of oral peptide administration through fundamental molecular structure modification
Solution Approach 2:
The patent addresses the short half-life issue by designing small molecules with resistance to rapid degradation, creating compounds that maintain therapeutic levels comparable to or exceeding injectable peptides despite oral administration challenges
3Duration of action of moving object
If GLP-1R agonists are made resistant to dipeptidyl peptidase 4 degradation, then duration of action is improved, but complexity of chemical structure increases
Solution Approach 1:
The patent applies parameter changes by systematically modifying chemical substituents at specific positions of the core molecular structure to optimize resistance against DPP-4 degradation while maintaining reasonable structural complexity and synthetic feasibility
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 provide effective treatment options for GLP-1R-mediated diseases and conditions, including NASH, obesity, and Type 2 diabetes, through oral administration, addressing the limitations of existing GLP-1R agonists.
Implementation Method 1
GLP-1 mediates intracellular signaling via the GLP-1 receptor (GLP-1R) which belongs to a family of G-protein coupled receptors that are present on the cell membrane and can result in accumulation of the secondary messenger cyclic adenosine monophosphate (cAMP) upon activation
Data Source
AI summary
The present disclosure provides GLP-1R agonists, and compositions, methods, and kits thereof. Such compounds are generally useful for treating a GLP-1R mediated disease or condition in a human.