GPR119 is a G protein-coupled receptor expressed on intestinal L cells that synthesize and secrete the blood glucose-lowering hormone glucagon-like peptide-1 (GLP-1)[1]. The GPR119 expression was markedly increased in preosteoclasts and then downregulated in mature osteoclasts. Activation of GPR119 with AS1269574 inhibited the generation of multinuclear osteoclasts from bone marrow-derived macrophages. GPR119 activation attenuated the expression of c-Fos and nuclear factor of activated T cells cytoplasmic 1 (NFATc1) and blocked RANKL-stimulated phosphorylation of IκBα, c-Jun N-terminal protein kinase (JNK), and extracellular signal-regulated kinase (ERK) but not p38[2]. AS1269574 is a potent, orally available GPR119 agonist. AS1269574 has the potential for the research of type 2 diabetes. AS1269574 had an EC(50) value of 2.5μM in HEK293 cells transiently expressing human GPR119 and enhanced insulin secretion in the mouse pancreatic β-cell line MIN-6 only under high-glucose (16.8mM) conditions. This contrasted with the action of the sulfonylurea glibenclamide, which also induced insulin secretion under low-glucose conditions (2.8mM). AS1269574 had an EC(50) value of 2.5μM in HEK293 cells transiently expressing human GPR119 and enhanced insulin secretion in the mouse pancreatic β-cell line MIN-6 only under high-glucose (16.8mM) conditions. This contrasted with the action of the sulfonylurea glibenclamide, which also induced insulin secretion under low-glucose conditions (2.8mM). In in vivo studies, a single administration of AS1269574 to normal mice reduced blood glucose levels after oral glucose loading based on the observed insulin secretion profiles. Significantly, AS1269574 did not affect fed and fasting plasma glucose levels in normal mice[3].
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