Abstract
We describe here a novel GPR119 agonist 24, which showed a potent and long-acting hypoglycemic effect in rats via oral dosing. For the discovery of 24, we chose compound 5, which possessed an oxadiazole linker, as a lead compound among our spirocyclic cyclohexane GPR119 agonist series, taking into account its lower plasma protein binding nature. 3,5-Difluoro and 4-methylsulfonylmethy groups on the left side phenyl group, and a gem-difluoro group on the right side of 24 are important for its agonist potency and metabolic stability, respectively.
Keywords:
GPR119 agonist; Spirocyclic.
Copyright © 2019 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Cyclohexanes / chemical synthesis
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Cyclohexanes / pharmacokinetics
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Cyclohexanes / pharmacology*
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Drug Stability
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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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Microsomes, Liver / metabolism
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Molecular Structure
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Oxadiazoles / chemical synthesis
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Oxadiazoles / pharmacokinetics
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Oxadiazoles / pharmacology*
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Rats, Sprague-Dawley
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Receptors, G-Protein-Coupled / agonists*
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Spiro Compounds / chemical synthesis
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / pharmacology*
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Structure-Activity Relationship
Substances
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Cyclohexanes
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GPR119 protein, human
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Hypoglycemic Agents
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Oxadiazoles
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Receptors, G-Protein-Coupled
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Spiro Compounds