Abstract
In the search for potent and selective human beta3-adrenergic receptor (AR) agonists as potential drugs for the treatment of obesity and noninsulin-dependent (type II) diabetes, a novel series of acetanilide-based analogues were prepared and their biological activities were evaluated at the human beta3-, beta2-, and beta1-ARs. Among these compounds, 2-pyridylacetanilide (2f), pyrimidin-2-ylacetanilide (2u), and pyrazin-2-ylacetanilide (2v) derivatives exhibited potent agonistic activity at the beta3-AR with functional selectivity over the beta1- and beta2-ARs. In particular, compound 2u was found to be the most potent and selective beta3-AR agonist with an EC(50) value of 0.11 microM and no agonistic activity for either the beta1- or beta2-AR. In addition, 2f, 2u, and 2v showed significant hypoglycemic activity in a rodent diabetic model.
MeSH terms
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Acetanilides / chemical synthesis
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Acetanilides / chemistry
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Acetanilides / pharmacology*
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Adrenergic beta-1 Receptor Agonists
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Adrenergic beta-2 Receptor Agonists
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Adrenergic beta-3 Receptor Agonists*
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Crystallography, X-Ray
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Dose-Response Relationship, Drug
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Drug Design*
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Humans
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Models, Molecular
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Molecular Conformation
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Pyrazines / chemical synthesis
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Pyrazines / chemistry
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Pyrazines / pharmacology*
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Pyridines / chemical synthesis
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Pyridines / chemistry
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Pyridines / pharmacology*
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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4'-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)-2-(2-pyridyl)acetanilide
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4'-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)-2-(pyrazin-2-yl)acetanilide
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4'-(2-((2-hydroxy-3-(4-hydroxyphenoxy)propyl)amino)ethyl)-2-(pyrimidin-2-yl)acetanilide
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Acetanilides
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Adrenergic beta-1 Receptor Agonists
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Adrenergic beta-2 Receptor Agonists
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Adrenergic beta-3 Receptor Agonists
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Pyrazines
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Pyridines
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Pyrimidines