Abstract
Benzyl and phenoxymethylene substituted oxadiazoles are potent and orally bioavailable beta3 adrenergic receptor (AR) agonists. The 4-trifluormethoxy substituted 5-benzyl oxadiazole 5f has an EC50 of 8 nM in the beta3 AR agonist assay with 100-fold selectivity over beta1 and beta2 AR binding inhibition activity. Its oral bioavailability in dogs is 30 +/- 4%, with a half-life of 3.8 +/- 0.4 h. In the anesthetized rhesus, 5f evoked a dose-dependent glycerolemia (ED50Gly = 0.15 mg/kg). Under these conditions a heart rate increase of 15% was observed at a dose level of 10 mg/kg.
MeSH terms
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Adrenergic beta-3 Receptor Agonists*
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Adrenergic beta-Agonists / chemical synthesis
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Adrenergic beta-Agonists / chemistry
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Adrenergic beta-Agonists / pharmacology*
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Animals
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Anti-Obesity Agents / chemical synthesis
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Anti-Obesity Agents / chemistry
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Anti-Obesity Agents / pharmacology*
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Biological Availability
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CHO Cells
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Cricetinae
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Dogs
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Drug Design
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Glycerol / metabolism
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Heart Rate / drug effects
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Humans
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Macaca mulatta
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Oxadiazoles / chemical synthesis
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Oxadiazoles / chemistry
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Oxadiazoles / pharmacology*
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
Substances
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Adrenergic beta-3 Receptor Agonists
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Adrenergic beta-Agonists
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Anti-Obesity Agents
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Oxadiazoles
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Sulfonamides
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Glycerol