Abstract
Compound 12 is a GPR40 agonist that realizes the full magnitude of efficacy possible via GPR40 receptor agonism. In vitro and in vivo studies demonstrated superior glucose lowering by 12 compared to fasiglifam (TAK-875), in a glucose dependent manner. The enhanced efficacy observed with the full agonist 12 was associated with both direct and indirect stimulation of insulin secretion.
Keywords:
GPCR; GPR40 full agonist; GSIS; Insulin secretagogues; Type 2 diabetes mellitus.
Copyright © 2018 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Benzofurans / pharmacology
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Biphenyl Compounds / pharmacology
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CHO Cells
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Cricetulus
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Dogs
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Glucagon-Like Peptide-1 Receptor / metabolism
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Glucuronides / biosynthesis
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Humans
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Hypoglycemic Agents / chemical synthesis
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / metabolism
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Hypoglycemic Agents / pharmacology*
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Macaca fascicularis
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Mice
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Microsomes, Liver / metabolism
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Molecular Docking Simulation
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Molecular Structure
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Phenylpropionates / pharmacology
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Piperidines / pharmacology
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Pyrazines / chemical synthesis
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Pyrazines / chemistry
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Pyrazines / metabolism
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Pyrazines / pharmacology*
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Pyrimidines / pharmacology
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Rats
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Receptors, G-Protein-Coupled / agonists*
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Structure-Activity Relationship
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Sulfones / pharmacology
Substances
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1-methylethyl 4-((7-(2-fluoro-4-(methylsulfonyl)phenyl)-6,7-dihydro-5H-pyrrolo(2,3-d)pyrimidin-4-yl)oxy)-1-piperidinecarboxylate
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3-cyclopropyl-3-(3-((2-(5,5-dimethylcyclopent-1-en-1-yl)-2'-fluoro-5'-methoxy-(1,1'-biphenyl)-4-yl)methoxy)phenyl)propanoic acid
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Benzofurans
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Biphenyl Compounds
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FFAR1 protein, human
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Ffar1 protein, mouse
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G-protein-coupled receptor 40, rat
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Glucagon-Like Peptide-1 Receptor
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Glucuronides
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Hypoglycemic Agents
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Phenylpropionates
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Piperidines
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Pyrazines
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Pyrimidines
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Receptors, G-Protein-Coupled
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Sulfones
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TAK-875