ACS Medicinal Chemistry Letters · 2022 · 11 citations · 20 references
PharmacyEndocrinologyPharmacologyDrug DesignDrug DiscoveryMetabolic RegulationDiabetes ManagementDiabetes MellitusGlucagon-like Peptide-1 Receptor AgonistsGlycemic ControlPeptide Drug DiscoveryWeight ManagementGlp-1 Receptor PharmacologyGlucagon Receptor AgonistsGlucagon-like Peptide 1 Receptor AgonismGlucagon-like PeptidesGlucose-dependent Insulin SecretionGlucose-stimulated Insulin SecretionIn Vivo StudiesIncretin Hormones
Peptide-based analogues of the gut-derived incretin hormone, glucagon-like peptide 1 (GLP1), stimulate insulin secretion in a glucose-dependent manner. Currently marketed GLP1 receptor (GLP1R) agonists are safe and effective in the management of Type 2 diabetes but often offer only modest weight loss. This has prompted the search for safe and effective alternatives to enhance the weight loss component of these treatments. We have demonstrated that concomitant activation GLP1R and the glucagon receptor (GCGR) can improve glucose metabolism and provide superior weight loss when compared to selective GLP1R agonism in preclinical species. This paper will highlight chemistry structure–activity relationship optimization and summarize in vivo efficacy studies toward the discovery of a once daily balanced dual agonist 12 (MK-1462), which was advanced into clinical trials.
20
A new glucagon and GLP-1 co-agonist eliminates obesity in rodents
Jonathan W. Day, Nickki Ottaway, James T Patterson et al. · Nature Chemical Biology · 2009 · 634 citations · Full text
Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in Mice
Alessandro Pocai, Paul E. Carrington, Jennifer R. Adams et al. · Diabetes · 2009 · 407 citations · Full text
Structure of the human glucagon class B G-protein-coupled receptor
Fai Siu, Min He, Chris de Graaf et al. · Nature · 2013 · 377 citations · Full text