Abstract
The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.
Keywords:
GDIR; GPR119 agonist; T2DM; Trans-1,4-dioxycyclohexane.
Copyright © 2015 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Blood Glucose / analysis
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Cyclohexanes / administration & dosage
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Cyclohexanes / chemistry*
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Cyclohexanes / pharmacokinetics
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Cyclohexanes / therapeutic use*
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Diabetes Mellitus, Type 2 / blood
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Diabetes Mellitus, Type 2 / drug therapy*
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Diabetes Mellitus, Type 2 / metabolism
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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 / pharmacokinetics
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Hypoglycemic Agents / therapeutic use*
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Male
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Mice
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Rats, Sprague-Dawley
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Rats, Zucker
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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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Cyclohexanes
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GPR119 protein, human
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Hypoglycemic Agents
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Receptors, G-Protein-Coupled