The role of pharmacology to produce firuglipel (DS-8500a), an orally available GPR119 agonist for type 2 diabetes mellitus

Abstract

GPR119 (G-protein coupled receptor 119) has been shown to be highly expressed in the lower small intestinal and colorectal L-cells and pancreatic β-cells, and mediates intracellular cAMP concentration, glucagon like peptide (GLP-1) secretion, and glucose stimulated insulin secretion (GSIS). As the next generation for the treatment of type 2 diabetes mellitus (T2DM), GPR119 agonist has been intensively studied by pharmaceutical companies and a lot of patents have been applied by them. In such highly competitive condition, biological differentiation and to find an advantage among GPR119 agonists were necessary to proceed the candidate compound in further clinical investigation. Firuglipel (DS-8500a) is an orally available GPR119 agonist synthesized in DAIICHI SANKYO CO., LTD (DS). It was originated from DS-chemical library and optimized in the aspect of bioavailability and safety. Firuglipel had a higher intrinsic activity (IA) of the production of intracellular cAMP in human GPR119 expressing CHO-K1 cells than those of other GPR119 agonists studied. The level of IA in each GPR119 agonist was correlated with the existence of agonist conformer. In parallel with the study for the differentiation from other GPR119 agonists, we compared firuglipel with dipeptidyl peptide-4 (DPP-4) inhibitor in NONcNZO10/LtJ mice and evaluated their combination in streptozotocin (STZ) treated C57BL/6J mice to clarify future positioning among anti-diabetics therapy. These pharmacological studies illustrated here can draw out a clinical value of compound and expected to lead the production of first-in-class agent in pharmaceutical companies.