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Updated: Jul 2, 2026

Homogeneous Time-resolved Förster Resonance Energy Transfer-based Assay for Detection of Insulin Secretion
Published on: May 10, 2018
Novel glucagon receptor antagonists with improved selectivity over the glucose-dependent insulinotropic polypeptide
János T Kodra1, Anker Steen Jørgensen, Birgitte Andersen
1Department of Diabetes Protein Engineering, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark. jtk@novonordisk.com
Abstract:
Optimization of a new series of small molecule human glucagon receptor (hGluR) antagonists is described. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closely related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtained compounds with low nanomolar affinities toward the hGluR, which were selective against the hGIPR and the human glucagon-like peptide-1 receptor (hGLP-1R). In the best cases, we obtained a >50 fold selectivity for the hGluR over the hGIPR and a >1000 fold selectivity over the hGLP-1R. A potent and selective glucagon receptor antagonist was demonstrated to inhibit glucagon-induced glycogenolysis in primary rat hepatocytes as well as to lower glucagon-induced hyperglycemia in Sprague-Dawley rats. Furthermore, the compound was shown to lower blood glucose in the ob/ob mouse after oral dosing.
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