Abstract
GPR119 is a 7-transmembrane receptor that is expressed in the enteroendocrine cells in the intestine and in the islets of Langerhans in the pancreas. Indolines and 6,7-dihydro-5H-pyrrolo[2,3-a]pyrimidines were discovered as G protein-coupled receptor 119 (GPR119) agonists, and lead optimization efforts led to the identification of 1-methylethyl 4-({7-[2-fluoro-4-(methylsulfonyl)phenyl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}oxy)-1-piperidinecarboxylate (GSK1104252A) (3), a potent and selective GPR119 agonist. Compound 3 showed excellent pharmacokinetic properties and sufficient selectivity with in vivo studies supporting a role for GPR119 in glucose homeostasis in the rodent. Thus, 3 appeared to modulate the enteroinsular axis, improve glycemic control, and strengthen previous suggestions that GPR119 agonists may have utility in the treatment of type 2 diabetes.
MeSH terms
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Administration, Oral
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Animals
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Cell Line
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Colon / metabolism
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Glucagon-Like Peptide 1 / metabolism
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Glucose / metabolism
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Glucose Tolerance Test
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology
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Incretins / metabolism
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Intestinal Mucosa / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacokinetics
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Pyrimidines / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / pharmacokinetics
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Pyrroles / pharmacology
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Rats
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Rats, Sprague-Dawley
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Rats, Wistar
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Receptors, G-Protein-Coupled / agonists*
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Stereoisomerism
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Structure-Activity Relationship
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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GPR119 protein, human
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Hypoglycemic Agents
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Incretins
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Piperidines
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Pyrimidines
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Pyrroles
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Receptors, G-Protein-Coupled
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Glucagon-Like Peptide 1
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Glucose