Double-acylated GLP-1 derivatives for oral bioavailability
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Solution Overview
Problem
Current GLP-1 derivatives face challenges in stability against gastrointestinal enzymes, pharmacokinetic profile, and oral bioavailability, limiting their effectiveness and administration routes.
Innovation Solution
Development of double-acylated GLP-1 derivatives with albumin binding moieties at positions 26 and 37, incorporating fatty diacids and fatty acids with phenyl or thiophene groups, which enhance stability, pharmacokinetic profile, and oral bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1 derivatives are designed with traditional structures, then they maintain basic biological activity, but they show poor stability against gastrointestinal enzymes and low oral bioavailability
Solution Approach 1:
The patent applies composite material principles by combining GLP-1 peptide with fatty acid moieties (such as octadecanoic acid, oleic acid, or elaidic acid) to create a hybrid molecule. This composite structure integrates the biological activity of GLP-1 with the stability and membrane-permeability properties of fatty acids, resulting in a derivative that resists gastrointestinal enzyme degradation and achieves oral bioavailability while maintaining pharmacological effectiveness.
Solution Approach 2:
The patent employs parameter changes by modifying the chemical structure of GLP-1 through acylation at specific positions (K26 and K37) with various fatty acid chains of different lengths and saturation levels. This systematic variation of structural parameters (chain length, saturation, position of acylation) allows optimization of both stability against enzymes and oral absorption properties, transforming the molecule's pharmacokinetic characteristics.
2Duration of action of moving object
If GLP-1 derivatives are acylated at position 26 and 37 with albumin binding moieties, then pharmacokinetic profile is prolonged and oral bioavailability increases, but molecular complexity increases
Solution Approach 1:
The patent applies universality by designing fatty acid moieties that perform multiple functions simultaneously: they serve as albumin binding domains to prolong circulation half-life, act as membrane permeability enhancers for oral absorption, and provide structural stability against enzymatic degradation. This multi-functional design achieves complex pharmacokinetic improvements without proportionally increasing molecular complexity.
Solution Approach 2:
The patent applies local quality by specifically targeting positions 26 and 37 of the GLP-1 peptide for acylation, rather than random modification. These specific locations were chosen because they allow attachment of albumin-binding fatty acid moieties without disrupting the core biological activity of the peptide. The modification is localized to specific residues, maintaining overall structural simplicity while achieving desired pharmacokinetic effects.
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 derivatives exhibit improved stability against gastrointestinal enzymes, prolonged pharmacokinetic profile, and increased oral bioavailability, making them suitable for subcutaneous, intravenous, and oral administration.
Implementation Method 1
Angewandte Chemie International Edition 2008, vol. 47, p. 3196-3201 reports the discovery and characterisation of a class of 4-(p-iodophenyl)butyric acid derivatives which purportedly display a stable noncovalent binding interaction with both mouse serum albumin (MSA) and human serum albumin (HSA).
Data Source
AI summary
The invention relates to a derivative of a GLP-1 analogue, which analogue comprises a first K residue at a position corresponding to position 37 of GLP-1 (7-37) (SEQ ID NO: 1), a second K residue at a position corresponding to position 26 of GLP-1 (7-37), and a maximum of ten amino acid modifications as compared to GLP-1 (7-37), wherein the first K residue is designated K37, and the second K residue is designated K26, which derivative comprises two albumin binding moieties attached to K26 and K37, respectively, wherein the albumin binding moiety comprises a protracting moiety selected from: Chem. 1: HOOC-(CH2)x-CO-* Chem. 2: HOOC-C6H4-O-(CH2)y-CO-* Chem. 3: R1-C6H4-(CH2)z-CO-* Chem. 4: HOOC-C4SH2-(CH2)w-CO-* in which x is an integer in the range of 6-18, y is an integer in the range of 3-17, z is an integer in the range of 1-5, R1 is a group having a molar mass not higher than 150 Da, and w is an integer in the range of 6-18; with the proviso that when the protracting moiety is Chem. 1, the albumin binding moiety further comprises a linker of formula Chem. 5: *-NH-(CH2)2-(O-(CH2)2)k-O-(CH2)n-CO-*, wherein k is an integer in the range of 1-5, and n is an integer in the range of 1-5; or a pharmaceutically acceptable salt, amide, or ester thereof. The invention also relates to the pharmaceutical use thereof, for example in the treatment and/or prevention of all forms of diabetes and related diseases, as well as to corresponding novel peptides and side chain intermediates. The derivatives are suitable for oral administration.