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Glucagon-like peptide 1 (GLP-1) is a 30 or 31 amino acid peptide hormone that contributes to the physiological regulation of glucose homeostasis and food intake. Herein, we report the discovery of a novel class of 11 amino acid GLP-1 receptor agonists. These peptides consist of a structurally optimized 9-mer, which is closely related to the N-terminal 9 amino acids of GLP-1, linked to a substituted C-terminal biphenylalanine (BIP) dipeptide. SAR studies resulted in 11-mer GLP-1R agonists with similar in vitro potency to the native 30-mer. Peptides 21 and 22 acutely reduced plasma glucose excursions and increased plasma insulin concentrations in a mouse model of diabetes. These peptides also showed sustained exposures over several hours in mouse and dog models. The described 11-mer GLP-1 receptor agonists represent a new tool in further understanding GLP-1 receptor pharmacology that may lead to novel antidiabetic agents.

Various N-substituted or unsubstituted aminomethyl crown ethers, which possess a reactive amino group, were prepared in good yields by the reaction between 3-amino-1,2-propanediols or aminomethyl oligoethylene glycols and oligoethylene glycol ditosylates or dichlorides. The scope of the reaction was investigated and the complexing ability of these new crown ether derivatives with sodium and potassium ions in methanol was measured by potentiometric titration.