research & technology
Small Molecule GLP-1
Agonist Program for type 2 diabetes
Type 2 diabetes mellitus is a metabolic disorder where disease progression is characterized by peripheral tissue insulin resistance, hyperglycemia, islet ß-cell compensation, hyperinsulinemia, dyslipidemia, increased liver gluconeogenesis and ultimate loss of β-cell mass and function. There is a growing epidemic of type 2 diabetes in the US and worldwide, mainly driven by the increase in obesity rates.
Prevention of diabetes is difficult and treatment is often managed with a combination of drugs including older classes like insulin sensitizers and secretagogues or hepatic glucose reducers, and newer drug classes including incretin enhancers (such as DPP-IV inhibitors) and incretin mimetics (such as Glucagon-like peptide (GLP) agonists).
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. A key function of endogenous GLP-1 is to activate its receptor, GLP-1R, on the pancreatic ß-cell to enhance glucose-dependent insulin secretion. Additional positive metabolic benefits of GLP-1 include suppression of excessive glucagon production, decreased food intake, delayed gastric emptying and improvement of ß-cell mass and function.
Several peptide GLP-1 agonists are current on the market. These peptides activate the GLP receptor and as a consequence, insulin release from the pancreatic beta cells is increased, glucagon is suppressed, and average blood glucose (HBa1c) is reduced. GLP-1R agonists also cause a decrease in gastric motility, which is likely the mechanism by which these agents cause weight loss effects. While this unique therapeutic profile is effective for treating type 2 diabetes, the major disadvantage of currently marketed GLP-1R peptide agonists are the need for injection. Receptos is engaged, through pursuit of the crystal structure of the GLP-1 receptor, in designing and developing a small molecule therapeutic to activate the GLP-1 receptor. The Receptos GPCR structure-based drug design platform may allow unique insight into GLP-1 receptor binding requirements, and structure determination may overcome the hurdles experienced by the pharmaceutical industry in designing a small molecule agonist compound to GLP-1. An orally bioavailable, potent, non-peptide agonist would make this important therapeutic class more convenient and accessible to a wider population of type 2 diabetes patients.