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, we prepared a novel series of phenoxypropanolamine derivatives containing the thiourea moiety and evaluated their biological activities at human beta3-, beta2-, and beta1-ARs. Among these compounds, 4-nitrophenylthiourea (18i) and 3-methoxyphenylthiourea (18k) derivatives were found to exhibit potent agonistic activity at the beta3-AR, with EC(50) values of 0.10 and 0.16 microM, respectively, and no agonistic activity for either the beta1- or beta2-AR. In addition, they showed significant hypoglycemic activity in a rodent diabetic model.
MeSH terms
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Adrenergic Agonists / chemical synthesis
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Adrenergic Agonists / chemistry*
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Adrenergic Agonists / pharmacology
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Adrenergic Agonists / therapeutic use*
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Adrenergic beta-3 Receptor Antagonists
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Animals
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Diabetes Mellitus, Type 2 / drug therapy*
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Humans
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Hypoglycemic Agents / chemical synthesis
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Hypoglycemic Agents / chemistry*
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Hypoglycemic Agents / pharmacology
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Hypoglycemic Agents / therapeutic use*
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Mice
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Molecular Structure
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Obesity / drug therapy
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Phenoxypropanolamines / chemical synthesis
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Phenoxypropanolamines / chemistry*
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Phenoxypropanolamines / pharmacology
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Phenoxypropanolamines / therapeutic use*
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Receptors, Adrenergic, beta / metabolism*
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Receptors, Adrenergic, beta-3 / metabolism
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Structure-Activity Relationship
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Thiourea / chemical synthesis
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Thiourea / chemistry
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Thiourea / pharmacology
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Thiourea / therapeutic use
Substances
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Adrenergic Agonists
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Adrenergic beta-3 Receptor Antagonists
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Hypoglycemic Agents
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Phenoxypropanolamines
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Receptors, Adrenergic, beta
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Receptors, Adrenergic, beta-3
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Thiourea