AS 1269574

AS 1269574,(2-[2-(4-bromophenyl)-6-methylpyrimidin-4-yl] amino ethanol), was capable of inducing glucose-stimulated insulin secretion (GSIS) and improved glucose tolerance in normal mice. AS 1269574 is an agonist of GPR119 with EC50 value of 2.5 µM [1] [2].

GPR119 is highly expressed in pancreatic β-cells. This receptor enhances the effect of GSIS via the elevation of intracellular cAMP concentrations [2].

Treated with either 1 or 10 µM AS 1269574 for 20 min, the insulin secretion of mouse pancreatic MIN-6 β-cells pre-exposed to 16.8 mM glucose was significantly increased compared with the DMSO vehicle control. In contrast, AS 1269574 did not affect the insulin release of MIN-6 cells previously treated with low-glucose (2.8 mM) [2].

In normal mice, a single treatment with 100 mg/kg of AS 1269574 significantly reduced the area under the curve (AUC) after 2 h (AUC0-2h) of blood glucose. AS 1269574 significantly increase the plasma insulin AUC0-2h in mice compared with the vehicle control. A single oral administration of 100 mg/kg AS 1269574 did not significantly lower the blood glucose AUC in either fasted or fed mice, indicating AS 1269574 did not have a hypoglycemic effect [2].

References:
[1].  Shigeru Yoshida, Hirotsugu Tanaka, Hiroyuki Oshima, et al. AS1907417, a novel GPR119 agonist, as an insulinotropic and β-cell preservative agent for the treatment of type 2 diabetes. Biochemical and Biophysical Research Communications, 2010, 400: 745-751.
[2].  Shigeru Yoshida, Takahide Ohishi, Tetsuo Matsui, et al. Identification of a novel GPR119 agonist, AS1269574, with in vitro and in vivo glucose-stimulated insulin secretion. Biochemical and Biophysical Research Communications, 2010, 400: 437-441.

Stimulation of proglucagon gene expression by human GPR119 in enteroendocrine L-cell line GLUTag.[Pubmed:23798572]

Mol Endocrinol. 2013 Aug;27(8):1267-82.

GPR119 is a G protein-coupled receptor expressed on enteroendocrine L-cells that synthesize and secrete the incretin hormone glucagon-like peptide-1 (GLP-1). Although GPR119 agonists stimulate L-cell GLP-1 secretion, there is uncertainty concerning whether GLP-1 biosynthesis is under the control of GPR119. Here we report that GPR119 is functionally coupled to increased proglucagon (PG) gene expression that constitutes an essential first step in GLP-1 biosynthesis. Using a mouse L-cell line (GLUTag) that expresses endogenous GPR119, we demonstrate that PG gene promoter activity is stimulated by GPR119 agonist AS1269574. Surprisingly, transfection of GLUTag cells with recombinant human GPR119 (hGPR119) results in a constitutive and apparently ligand-independent increase of PG gene promoter activity and PG mRNA content. These constitutive actions of hGPR119 are mediated by cAMP-dependent protein kinase (PKA) but not cAMP sensor Epac2. Thus, the constitutive action of hGPR119 to stimulate PG gene promoter activity is diminished by: 1) a dominant-negative Galphas protein, 2) a dominant-negative PKA regulatory subunit, and 3) a dominant-negative A-CREB. Interestingly, PG gene promoter activity is stimulated by 6-Bn-cAMP-AM, a cAMP analog that selectively activates alpha and beta isoforms of type II, but not type I PKA regulatory subunits expressed in GLUTag cells. Finally, our analysis reveals that a specific inhibitor of Epac2 activation (ESI-05) fails to block the stimulatory action of 6-Bn-cAMP-AM at the PG gene promoter, nor is PG gene promoter activity stimulated by: 1) a constitutively active Epac2, or 2) cAMP analogs that selectively activate Epac proteins. Such findings are discussed within the context of ongoing controversies concerning the relative contributions of PKA and Epac2 to the control of PG gene expression.

Identification of a novel GPR119 agonist, AS1269574, with in vitro and in vivo glucose-stimulated insulin secretion.[Pubmed:20804735]

Biochem Biophys Res Commun. 2010 Sep 24;400(3):437-41.

The G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic beta-cells. On activation, this receptor enhances the effect of glucose-stimulated insulin secretion (GSIS) via the elevation of intracellular cAMP concentrations. Although GPR119 agonists represent promising oral antidiabetic agents for the treatment of type 2 diabetes therapy, they suffer from the inability to adequately directly preserve beta-cell function. To identify a new structural class of small-molecule GPR119 agonists with both GSIS and the potential to preserve beta-cell function, we screened a library of synthetic compounds and identified a candidate molecule, AS1269574, with a 2,4,6-tri-substituted pyrimidine core. Here, we examined the preliminary in vitro and in vivo effects of AS1269574 on insulin secretion and glucose tolerance. AS1269574 had an EC(50) value of 2.5muM in HEK293 cells transiently expressing human GPR119 and enhanced insulin secretion in the mouse pancreatic beta-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. Taken together, these results suggest that AS1269574 represents a novel structural class of small molecule, orally administrable GPR119 agonists with GSIS and promising potential for the treatment of type 2 diabetes.