| Identification of a novel GPR119 agonist, AS1269574, with in vitro and in vivo glucose-stimulated insulin secretion. | |
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MedLine Citation:
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PMID: 20804735 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The G protein-coupled receptor 119 (GPR119) is highly expressed in pancreatic β-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 β-cell function. To identify a new structural class of small-molecule GPR119 agonists with both GSIS and the potential to preserve β-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 2.5μM 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. 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. |
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Authors:
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Shigeru Yoshida; Takahide Ohishi; Tetsuo Matsui; Masayuki Shibasaki |
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Publication Detail:
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Type: Journal Article Date: 2010-09-16 |
Journal Detail:
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Title: Biochemical and biophysical research communications Volume: 400 ISSN: 1090-2104 ISO Abbreviation: Biochem. Biophys. Res. Commun. Publication Date: 2010 Sep |
Date Detail:
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Created Date: 2010-09-27 Completed Date: 2010-10-13 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372516 Medline TA: Biochem Biophys Res Commun Country: United States |
Other Details:
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Languages: eng Pagination: 437-41 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan. shigeru.yoshida@jp.astellas.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blood Glucose / drug effects Cell Line Ethanolamines / chemistry, isolation & purification, pharmacology* Fasting Glucose / pharmacology* Humans Hypoglycemic Agents / chemistry, pharmacology* Insulin / secretion* Insulin-Secreting Cells / drug effects*, secretion Mice Mice, Inbred ICR Pyrimidines / chemistry, isolation & purification, pharmacology* Receptors, G-Protein-Coupled / agonists* |
| Chemical | |
Reg. No./Substance:
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0/2-(2-(4-bromophenyl)-6-methylpyrimidin-4-yl)aminoethanol; 0/Blood Glucose; 0/Ethanolamines; 0/GPR119 protein, human; 0/Gpr119 protein, mouse; 0/Hypoglycemic Agents; 0/Pyrimidines; 0/Receptors, G-Protein-Coupled; 11061-68-0/Insulin; 50-99-7/Glucose |
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