Liraglutide Side Chain [Pal-Glu(OSu)-OtBu]

Liraglutide Side Chain [Pal-Glu(OSu)-OtBu] is a key chemical intermediate used in the synthesis of Liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist employed in type 2 diabetes treatment. It features a palmitoyl-modified glutamic acid residue where the palmitic acid provides a lipophilic anchor for albumin binding, improving the drug’s half-life. The gamma carboxyl is activated as an NHS ester (OSu) for efficient conjugation to lysine residues during peptide synthesis, while the alpha carboxyl is protected by a tert-butyl ester (OtBu) to prevent side reactions and allow selective deprotection.

Appearance

• White to off-white solid or lyophilized powder.

Source

• Synthetic, produced by specialized peptide synthesis or custom synthesis laboratories.

Molecular Weight and Structure

• Approximate molecular weight: 640–660 g/mol (depending on salt form).

• Structure consists of:

  • Glutamic acid core

  • Palmitoyl group attached to alpha-amino

  • Gamma carboxyl activated NHS ester (OSu)

  • Alpha carboxyl tert-butyl ester (OtBu)

Biological Activity

• Inactive standalone; biologically active as part of the full Liraglutide molecule.

• Palmitoylation enhances albumin binding and prolongs drug action.

Purity and Microbial Contamination

• Purity: ≥95% to ≥98% by HPLC, critical for synthesis quality.

• Minimal microbial contamination; low endotoxin levels important for manufacturing.

Identity and Quality Control

• Confirmed by Mass Spectrometry and NMR.

• Purity by HPLC, water content by Karl Fischer titration, specific rotation for chirality, elemental analysis.

Shelf Life and Storage

 

Applications

• Building block for chemically synthesizing Liraglutide.

• Enables site-specific palmitoylation on peptide backbone.

• Enhances pharmacokinetics via albumin binding.

Key Characteristics

• Palmitoylation moiety critical for albumin affinity.

• NHS ester facilitates efficient coupling to lysine ε-amino groups.

• OtBu protects alpha carboxyl during peptide synthesis.

• High purity essential for therapeutic manufacturing.

• Soluble in organic solvents like DMF, DMSO, acetonitrile.

Citation 

• Knudsen LB. “Liraglutide: a new once-daily human GLP-1 analogue.” Eur J Endocrinol. 2004;151(Suppl 3):U13-8.

• Lau J, Bloch P, Schäffer L, et al. “Discovery of an acylated human glucagon-like peptide-1 receptor agonist.” J Med Chem. 2005;48(25):7370-80.

• Meier JJ. “GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.” Nat Rev Endocrinol. 2012;8(12):728-42.

• Mahapatra MK, Karuppasamy M, Sahoo BM. “Glucagon-like peptide-1 receptor agonists in type 2 diabetes.” J Pharm Bioallied Sci. 2012;4(Suppl 1):S61.

• Owens DR. “Clinical potential of long-acting GLP-1 receptor agonists.” Diabetes Obes Metab. 2015;17(7):629-42.

• Göke R, Larsen MO. “The pharmacological profile of liraglutide.” Eur J Endocrinol. 2010;162(Suppl 1):S5-9.

• Kim W, Egan JM. “The role of incretins in glucose homeostasis and diabetes treatment.” Pharmacol Rev. 2008;60(4):470-512.

• Garber A. “Long-acting glucagon-like peptide 1 receptor agonists.” Diabetes Obes Metab. 2011;13(8):689-707.

• Novo Nordisk. Victoza (liraglutide [rDNA origin] injection) prescribing info. 2010.

• Brand CL, Trevaskis NL, Watts GF. “Optimising clinical use of GLP-1 receptor agonists.” Diabetes Metab Syndr Obes. 2016;9:207-18.