Abstract
A cloned human beta 3 adrenergic receptor assay was used to identify phenoxypropanolamine agonist 1. SAR studies led to the identification of benzenesulfonamide derivative 20, a 6.3 nM beta 3 agonist which shows 30-fold selectivity for beta 3 agonist activity over beta 1 and beta 2 receptor binding. Further refinement of this lead provided 4-bromo derivative 39, a subnanomolar agonist with 660-fold and 230-fold selectivity over beta 1 and beta 2, respectively.
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 / pharmacology
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Benzenesulfonamides
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Cloning, Molecular
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Drug Design
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Humans
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Molecular Conformation
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Molecular Structure
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Propanolamines / chemical synthesis*
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Propanolamines / chemistry*
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Propanolamines / pharmacology
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Receptors, Adrenergic, beta / drug effects*
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Receptors, Adrenergic, beta / physiology
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Receptors, Adrenergic, beta-1 / drug effects
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Receptors, Adrenergic, beta-2 / drug effects
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Receptors, Adrenergic, beta-3
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Recombinant Proteins / drug effects
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Recombinant Proteins / metabolism
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Stereoisomerism
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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-Agonists
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Propanolamines
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Receptors, Adrenergic, beta
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Receptors, Adrenergic, beta-1
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Receptors, Adrenergic, beta-2
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Receptors, Adrenergic, beta-3
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Recombinant Proteins
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Sulfonamides
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CGP 12177