Design, synthesis, and biological evaluation of 2‐(4‐(methylsulfonyl)phenyl)pyridine derivatives as GPR119 agonists

Abstract

This study describes the design, synthesis, and biological evaluation of a series of novel small molecule GPR119 agonists with improved potency and moderate physiochemical characteristics. Among them, the most promising compounds 19 and 20 were obtained with EC values of 75 and 25 nM, respectively, in vitro cAMP assays and effectively decreased blood glucose excursion in oral glucose tolerance test (OGTT) of normal mice. Furthermore, in OGTT with type 2 diabetic mice induced by streptozotocin and high-fat diet, compound 19 also showed significant reduction in blood glucose level compared to vehicle control group, which demonstrated an attractive in vitro and in vivo profile for further development.

Optimisation of novel 4, 8-disubstituted dihydropyrimido[5,4-b][1,4]oxazine derivatives as potent GPR 119 agonists

“…G protein-coupled receptor 119 (GPR119) is a member of class A (rhodopsin-type) GPCR family, with highly expressed in pancreatic b-cells and the K and L cells of the gastrointestinal tract [7][8][9] . Activation of GPR119 increases the intracellular cyclic AMP (cAMP) level, which in turn directly stimulate the glucose-dependent insulin secretion and regulate glucagon-like peptide 1 (GLP-1), leading to improve the glucose tolerance in T2DM patients [10][11][12][13][14] . In addition, GPR119 agonists showed b-cells function preservation, which is also an important role in current T2DM therapy [15][16][17] .…”