Abstract
GPR142 is a novel GPCR that is predominantly expressed in pancreatic β-cells. GPR142 agonists potentiate glucose-dependent insulin secretion, and therefore can reduce the risk of hypoglycemia. Optimization of our lead pyridinone-phenylalanine series led to a proof-of-concept compound 22, which showed in vivo efficacy in mice with dose-dependent increase in insulin secretion and a decrease in glucose levels.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Blood Glucose / analysis
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Diabetes Mellitus, Type 2 / drug therapy*
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Dose-Response Relationship, Drug
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Drug Stability
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Glucose Tolerance Test
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HEK293 Cells
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Humans
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Hypoglycemic Agents / administration & dosage
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology*
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Insulin / blood
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Insulin / metabolism
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Insulin Secretion
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Male
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Mice
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Mice, Inbred Strains
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Microsomes / chemistry
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Phenylalanine / administration & dosage
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Phenylalanine / chemistry
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Phenylalanine / pharmacology*
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Rats
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / metabolism
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Structure-Activity Relationship
Substances
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Blood Glucose
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GPR142 protein, human
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GPR142 protein, mouse
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Hypoglycemic Agents
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Insulin
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Receptors, G-Protein-Coupled
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Phenylalanine