GLP-1R/GIPR Agonist Synthesis With High-Purity Amide Coupling
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
There is a need for chemical entities that modulate the activity of GLP-1R and/or GIPR and for improved methods of synthesizing such chemical entities.
Innovation Solution
A method of synthesizing N-terminal conjugated peptidyl compounds using specific amide bond-forming conditions and reagents, such as 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU) or a combination of ethyl cyano (hydroxyimino) acetate (OxymaPure™) and N,N′-diisopropylcarbodiimide (DIC), to create GLP-1R/GIPR agonists with enhanced purity and yield.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Manufacturing precision
If conventional amide bond-forming conditions are used in solid-phase peptide synthesis, then the synthesis process is simpler, but the purity and yield of the final GLP-1R/GIPR agonist product are reduced
Solution Approach 1:
The patent applies parameter changes by modifying the amide bond-forming conditions through specific reagent selection (TBTU or OxymaPure/DIC combination), controlled reaction temperatures (0°C to room temperature), and optimized reaction times (1-24 hours). These parameter adjustments directly improve the purity and yield of the GLP-1R/GIPR agonist while maintaining manageable procedural complexity
Solution Approach 2:
The patent uses coupling reagents as intermediaries to facilitate the amide bond formation between the resin-bound peptide and the amino acid derivative. Specifically, TBTU or the OxymaPure/DIC combination acts as a mediator to enable efficient and high-yielding coupling reactions, improving manufacturing precision without requiring overly complex direct reaction conditions
2Manufacturing precision
If resin-bound peptide synthesis is used, then the peptide can be purified during synthesis, but the deprotection and coupling steps become more time-consuming
Solution Approach 1:
The patent employs preliminary action through Fmoc pre-protection of amino acids before resin binding. This pre-protection strategy allows for streamlined deprotection steps during synthesis, where the Fmoc group can be efficiently removed with piperidine to expose the amine for subsequent coupling, thereby reducing overall synthesis time while maintaining the purification advantages of solid-phase synthesis
Solution Approach 2:
The patent maintains continuity of useful action by implementing iterative cycles of deprotection and coupling on the resin-bound peptide. Each cycle continuously builds the peptide chain with integrated purification, avoiding time-consuming isolation and re-dissolution steps. The resin-bound intermediate remains in place throughout synthesis, enabling continuous productive action
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 method produces GLP-1R/GIPR agonists with improved handleability, purity, and yield, effectively agonizing the activities of GLP-1 and GIP, and potentially treating diabetes-related complications.
Implementation Method 1
reacting the product of step (i) with 2-((2-oxo-2-((2-(2-oxopiperidin-1-yl)ethyl)amino)ethyl)thio)acetic acid (III) under amide bond-forming conditions, wherein the amide bond-forming conditions comprise use of 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU)
Data Source
AI summary
The present disclosure provides novel synthetic methods for preparing GLP-1R/GIPR agonists.