GLP1R Agonists

Diabetes

Type II diabetes mellitus is a metabolic disorder where disease progression is characterized by peripheral tissue insulin resistance, hyperglycemia, islet β-cell compensation, hyperinsulinemia, dyslipidemia, increased liver gluconeogenesis and ultimate loss of β-cell mass and function.  The pathophysiological consequences of aberrant glucose and lipid metabolism are toxicity to organs including the kidney, eye, peripheral neurons, vasculature and heart.  In particular, there is significant unmet medical need for new agents that delay disease progression by improving glycemic control and β-cell mass and function.

Glucagon-like peptide-1 (GLP-1) is a member of the incretin family of neuroendocrine peptide hormones secreted from L-cells of the intestine in response to food ingestion.  GLP-1 has multiple metabolic effects that are attractive for an anti-diabetic agent. A key function of GLP-1 is to activate its receptor, GLP-1R, on the pancreatic β-cell to enhance glucose-dependent insulin secretion.  Additional positive metabolic benefits of GLP-1 include suppression of excessive glucagon production, decrease food intake, delay gastric emptying, and improvement of b-cell mass and function. Unfortunately, the rapid proteolysis of GLP-1 in blood limits its use as a therapeutic agent.

Validation of GLP-1R agonists as a therapeutic modality was achieved by Exendin-4 (Byetta^TM), a peptide GLP-1 receptor agonist recently approved for the treatment of Type II diabetes mellitus. Dosing of Exendin-4 by subcutaneous administration lowers blood glucose and decreases HbA1c levels. Therefore, an oral GLP-1 receptor agonist would provide glycemic control while offering the convenience of oral dosing.