Double-acylated GLP-1 derivatives with protracting moieties
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Solution Overview
Problem
Current GLP-1 derivatives have limitations in terms of pharmacokinetic profile, oral bioavailability, and biophysical properties, which affect their efficacy and administration routes for treating diabetes and related diseases.
Innovation Solution
Development of double-acylated GLP-1 derivatives with specific modifications at lysine residues, incorporating protracting moieties linked via ethylene glycol units, to enhance pharmacokinetic profile, oral bioavailability, and biophysical properties, allowing for subcutaneous, intravenous, and oral administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Duration of action of moving object
If GLP-1 derivatives are modified with protracting moieties at lysine residues, then pharmacokinetic profile is prolonged and oral bioavailability is improved, but structural complexity increases
Solution Approach 1:
The modification is divided into discrete segments: protracting moieties (fatty acids or fatty diacids) linked via linkers to specific lysine residues. This segmentation allows independent optimization of each component's contribution to pharmacokinetics while managing overall structural complexity through modular design.
Solution Approach 2:
The patent systematically varies parameters such as the type of protracting moiety (fatty acid vs. fatty diacid), linker structure (ethylene glycol units), and lysine residue positions (K18, K26, K37) to optimize the pharmacokinetic profile. This parameter change approach enables tuning of duration of action and oral bioavailability without requiring entirely new molecular architectures.
2Reliability
If double acylation is performed at lysine residues, then oral bioavailability and biophysical properties are improved, but manufacturing complexity increases
Solution Approach 1:
The peptide sequence is pre-designed to include lysine residues at specific positions (K18, K26, or K37) that are predetermined as suitable for acylation. This preliminary planning ensures that the double acylation process can be efficiently executed during peptide synthesis without requiring complex post-synthesis modifications, thereby improving manufacturability while achieving high oral bioavailability.
3Reliability
If protracting moieties with phenyl or phenoxy groups are incorporated, then binding affinity to albumin is enhanced, but synthesis complexity increases
Solution Approach 1:
The phenyl or phenoxy groups are introduced only at specific locations where they are most effective for albumin binding, rather than throughout the entire molecule. This localized modification approach enhances binding affinity at critical interaction sites while minimizing the overall synthesis complexity by avoiding unnecessary modifications in regions where the phenyl groups would not contribute to binding.
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 18 of GLP-1 (7-37) (SEQ ID NO: 1 ), a second K residue at another position, and a maximum of twelve amino acid changes as compared to GLP-1 (7-37); which derivative comprises two protracting moieties attached to said first and second K residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 1, Chem. 2, and Chem. 3: Chem. : HOOC-(CH2)x-CO-* Chem. 2: HOOC-C6H4-0-(CH2)y-CO-* Chem. 3: R2-C6H4-(CH2)z-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, and R2 is a group having a molar mass not higher than 150 Da; and the linker comprises Chem. 4: *-NH-(CH2)2-(0-(CH2)2)k-0-(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.