Structure-activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: importance of fatty acid length, polarity, and bulkiness

Kjeld Madsen; Lotte Bjerre Knudsen; Henrik Agersoe; Per Franklin Nielsen; Henning Thøgersen; Michael Wilken; Nils Langeland Johansen

doi:10.1021/jm070861j

Structure-activity and protraction relationship of long-acting glucagon-like peptide-1 derivatives: importance of fatty acid length, polarity, and bulkiness

J Med Chem. 2007 Nov 29;50(24):6126-32. doi: 10.1021/jm070861j. Epub 2007 Nov 2.

Authors

Kjeld Madsen¹, Lotte Bjerre Knudsen, Henrik Agersoe, Per Franklin Nielsen, Henning Thøgersen, Michael Wilken, Nils Langeland Johansen

Affiliation

¹ Department of Protein Engineering, Novo Nordisk, Novo Nordisk Park, Maaloev, Denmark.

PMID: 17975905
DOI: 10.1021/jm070861j

Abstract

We here report a series of derivatives describing the structure-activity relationship around liraglutide, a once-daily human glucagon-like peptide-1 fatty acid derivative, with respect to potency as well as protraction in vivo. The spacer region between the fatty acid and the peptide is mostly important for potency, whereas the fatty acid or fatty acid mimetic is important for both potency and protraction. The length of the fatty acid is the most important parameter for protraction.

MeSH terms

Amino Acid Sequence
Animals
Cell Line
Cricetinae
Cyclic AMP / biosynthesis
Fatty Acids / chemical synthesis*
Fatty Acids / chemistry
Fatty Acids / pharmacokinetics
Fatty Acids / pharmacology
Glucagon-Like Peptide 1 / analogs & derivatives*
Glucagon-Like Peptide 1 / chemical synthesis
Glucagon-Like Peptide 1 / chemistry
Glucagon-Like Peptide 1 / pharmacokinetics
Glucagon-Like Peptide 1 / pharmacology
Glucagon-Like Peptide-1 Receptor
Humans
Liraglutide
Molecular Sequence Data
Receptors, Glucagon / agonists
Structure-Activity Relationship
Swine

Substances

Fatty Acids
GLP1R protein, human
Glucagon-Like Peptide-1 Receptor
Receptors, Glucagon
Liraglutide
Glucagon-Like Peptide 1
Cyclic AMP