GLP-1 Ester Prodrugs With Dipeptide Extension For Prolonged Half-Life
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Solution Overview
Problem
Current GLP-1 peptide hormones have a short half-life in plasma, limiting their therapeutic effectiveness, and existing prodrugs do not effectively extend their biological activity and stability against degradation.
Innovation Solution
Development of ester prodrugs with a dipeptide extension attached to the N-terminus of GLP-1 via an ester bond, where the alpha-amino group is modified to a hydroxyl group, allowing for slow biotransformation into a modified parent drug that is stabilized against DPP-IV degradation and has an extended half-life.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If GLP-1 peptide hormone is used directly, then immediate therapeutic effect is achieved, but half-life in plasma is very short
Solution Approach 1:
The patent applies preliminary action by creating a prodrug form of GLP-1 that is prepared in advance with a modified N-terminus (hydroxyl group instead of alpha-amino group) and attached to a dipeptide extension via ester bond. This preliminary modification allows the drug to be stored and administered in a stable form that will gradually transform into the active drug in the body, thereby extending the duration of action while maintaining therapeutic effectiveness.
Solution Approach 2:
The patent applies parameter changes by modifying the chemical structure of GLP-1 at the N-terminus, specifically changing the alpha-amino group to a hydroxyl group and attaching a dipeptide extension via ester bond. This structural parameter change fundamentally alters the pharmacokinetic properties, extending the half-life from minutes to hours while preserving the biological activity through controlled biotransformation.
2Duration of action of moving object
If existing prodrug derivatisation techniques (albumin binding, PEGylation) are used, then half-life is prolonged, but stability against degradation and biological activity extension are insufficient
Solution Approach 1:
The patent applies segmentation by dividing the prodrug structure into distinct functional components: the modified GLP-1 peptide core (with hydroxyl group at N-terminus), the ester bond linker, and the dipeptide extension. This segmented structure allows each component to perform its specific function - the modified core provides stability, the ester bond enables controlled hydrolysis, and the dipeptide extension prolongs half-life through gradual release, collectively achieving both stability and extended biological half-life.
Solution Approach 2:
The patent applies the intermediary principle by using the ester bond as a mediator between the modified GLP-1 peptide and the dipeptide extension. This ester bond acts as a controllable link that is stable enough to maintain the prodrug structure during circulation but can be hydrolyzed by esterases in the body to release the active drug, thereby mediating between stability and biological activity extension.
3Duration of action of moving object
If ester prodrug with dipeptide extension is used, then sustained release and extended half-life are achieved, but conversion rate and speed of biotransformation may be reduced
Solution Approach 1:
The patent applies dynamics by designing a biotransformation system that is not static but dynamically adapts to physiological conditions. The ester bond hydrolysis rate is influenced by local esterase concentration, pH, and other biological factors, allowing the conversion speed to be optimized in different physiological environments. This dynamic characteristic enables sustained release over extended periods while maintaining adequate conversion speed when needed.
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 ester prodrugs provide a sustained release of the active GLP-1 peptide with improved stability and prolonged biological activity, enhancing the therapeutic window and duration of action, and are suitable for various administration routes including subcutaneous, intravenous, and oral administration.
Implementation Method 1
The ester bond may be at the N-terminus of the peptide drug... a nucleophile component of the dipeptide (for example an amine nucleophile) cleaves the ester bond with the formation of the corresponding diketopiperazine derivative and the parent drug
Data Source
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AI summary
The invention relates to a GLP-1 prodrug of the general formula I: R1-(NHXaa1)- Xaa2-(OHis)-(GLP-1peptide) (Formula I), wherein GLP-1 peptide is GLP-1(8-37) (SEQ ID NO: 1) or an analogue thereof having a maximum of nineamino acid changes as compared to GLP-1(8-37), R1 is lower alkyl, (NHXaa1) is an amino acid, Xaa2 is an amino acid, and (OHis) is a radical of imidazole-lactic acid; or a pharmaceutically acceptable salt, amide, or ester of the prodrug. The invention also relates to specific GLP-1 parent drugs of the general formula II: (HOHis)-(GLP-1peptide) (Formula II), as well as specific intermediate products. The invention furthermore relates to a method of achieving release in vivo of an active and stabilised GLP-1 parent drug of the general formula II: (HOHis)-(GLP-1 peptide), by administering a GLP-1 prodrug; as well as to such GLP-1 prodrug, and such GLP-1 parent drug, respectively, for use as a medicament, in particular for use in the treatment and/or prevention of all forms of diabetes and related diseases. The prodrug may be used to alter the PK and/or absorption profile of the drug, for example to a desirable bell-shaped curve. The parent drug has a good biological activity, and is stabilised against degradation by DPP- IV.