Novel Small Molecule Glucagon-Like Peptide-1 Receptor Agonist Stimulates Insulin Secretion in Rodents and From Human Islets

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 12; pp. 3099 - 3107
• Main Authors: Sloop, Kyle W., Willard, Francis S., Brenner, Martin B., Ficorilli, James, Valasek, Kathleen, Showalter, Aaron D., Farb, Thomas B., Cao, Julia X.C., Cox, Amy L., Michael, M. Dodson, Gutierrez Sanfeliciano, Sonia Maria, Tebbe, Mark J., Coghlan, Michael J.
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.12.2010
• Subjects: Agonists (Biochemistry); Animals; Care and treatment; Catheters; Cyclic AMP - metabolism; Development and progression; Diabetes; Diabetes therapy; Gastric Inhibitory Polypeptide - pharmacology; Genes, Reporter; Glucagon; Glucagon - pharmacology; Glucagon-Like Peptide 1 - physiology; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Health aspects; Hormones; Humans; Hyperglycemia; Insulin; Insulin - metabolism; Insulin Secretion; Islet Studies; Islets of Langerhans - cytology; Islets of Langerhans - drug effects; Islets of Langerhans - metabolism; Laboratory animals; Ligands; Luciferases - genetics; Male; Molecular weight; Parathyroid Hormone - pharmacology; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Glucagon - agonists; Receptors, Glucagon - genetics; Research design; Rodents; Type 2 diabetes; Vasoactive Intestinal Peptide - pharmacology; United States; United States > US; Indianapolis Indiana
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db10-0689

The clinical effectiveness of parenterally-administered glucagon-like peptide-1 (GLP-1) mimetics to improve glucose control in patients suffering from type 2 diabetes strongly supports discovery pursuits aimed at identifying and developing orally active, small molecule GLP-1 receptor agonists. The purpose of these studies was to identify and characterize novel nonpeptide agonists of the GLP-1 receptor. Screening using cells expressing the GLP-1 receptor and insulin secretion assays with rodent and human islets were used to identify novel molecules. The intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp characterized the insulinotropic effects of compounds in vivo. Novel low molecular weight pyrimidine-based compounds that activate the GLP-1 receptor and stimulate glucose-dependent insulin secretion are described. These molecules induce GLP-1 receptor-mediated cAMP signaling in HEK293 cells expressing the GLP-1 receptor and increase insulin secretion from rodent islets in a dose-dependent manner. The compounds activate GLP-1 receptor signaling, both alone or in an additive fashion when combined with the endogenous GLP-1 peptide; however, these agonists do not compete with radiolabeled GLP-1 in receptor-binding assays. In vivo studies using the IVGTT and the hyperglycemic clamp in Sprague Dawley rats demonstrate increased insulin secretion in compound-treated animals. Further, perifusion assays with human islets isolated from a donor with type 2 diabetes show near-normalization of insulin secretion upon compound treatment. These studies characterize the insulinotropic effects of an early-stage, small molecule GLP-1 receptor agonist and provide compelling evidence to support pharmaceutical optimization.