GPR119 agonists: a promising new approach for the treatment of type 2 diabetes and related metabolic disorders.
Type 2 diabetes (T2D) and associated obesity have reached epidemic proportions, and there is an increasing need for orally effective agents that regulate glucose homeostasis with a concurrent reduction in body weight. GPR119, a class-A (rhodopsin-like) G protein-coupled receptor, expressed primarily in the human pancreas and gastrointestinal tract, has attracted considerable interest as a T2D drug target in the last three to five years. The activation of GPR119 increases the intracellular accumulation of cAMP, leading to enhanced glucose-dependent insulin secretion and increased levels of the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (glucose-dependent insulinotropic peptide). In rodent models, orally available GPR119-specific agonists have been shown to attenuate blood glucose levels with a simultaneous body weight loss. This review summarizes the research leading to the identification of GPR119 as a potential drug target for T2D and related metabolic disorders. In addition, an overview of the recent progress made in the discovery of orally active GPR119 agonists is provided.
Shah
Unmesh
U
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. unmesh.shah@spcorp.com
D000818:Animals; D002986:Clinical Trials as Topic; D000242:Cyclic AMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008659:Metabolic Diseases / Q000188:drug therapy / Q000378:metabolism; D015394:Molecular Structure; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D054852:Small Molecule Libraries / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
C519854:GPR119 protein, human; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D000242:Cyclic AMP