Abstract
In search of potent and selective human beta(3) agonists as potential drugs for the treatment of human obesity and type II diabetes, a series of (4-piperidin-1-yl)phenyl amides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor. The leucine derivative 26e and the reverse amide 33b were found to be the two most potent and selective compounds in this study. With EC(50) values of 0.008 and 0.009 microM, respectively, at the beta(3) receptor, nearly completely abolished intrinsic activity at either the beta(1) or beta(2) receptor, and significant thermogenesis effects on human beta(3)-adrenergic receptor transgenic mice, 26e and33b are among the most potent and selective human beta(3) agonists known to date.
MeSH terms
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Adrenergic beta-Agonists / chemical synthesis*
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Adrenergic beta-Agonists / chemistry
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Adrenergic beta-Agonists / metabolism
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Adrenergic beta-Agonists / pharmacology
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Animals
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Body Temperature / drug effects
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CHO Cells
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Cricetinae
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Cyclic AMP / metabolism
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Energy Metabolism / drug effects
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Female
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Humans
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Leucine / analogs & derivatives
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Leucine / chemical synthesis*
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Leucine / chemistry
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Leucine / metabolism
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Leucine / pharmacology
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Mice
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Mice, Transgenic
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / metabolism
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Piperidines / pharmacology
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Radioligand Assay
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Receptors, Adrenergic, beta-3 / metabolism*
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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 / metabolism
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Sulfonamides / pharmacology
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Transfection
Substances
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3-(butyl-4-(4-((2-hydroxy-2-(4-hydroxy-3-((methylsulfonyl)amino)phenyl)ethyl)amino)-1-piperidinyl)anilino)-3-oxopropanoic acid
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Adrenergic beta-Agonists
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N-(4-(4-((2-hydroxy-2-(4-hydroxy-3-((methylsulfonyl)amino)phenyl)ethyl)amino)-1-piperidinyl)benzoyl)leucine
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Piperidines
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Receptors, Adrenergic, beta-3
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Sulfonamides
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Cyclic AMP
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Leucine