Efficient conversion of a nonselective norepinephrin reuptake inhibitor into a dual muscarinic antagonist-β₂-agonist for the treatment of chronic obstructive pulmonary disease

Following interrogation of a wide-ligand profile database, a nonselective norepinephrin reuptake inhibitor was converted into a novel muscarinic antagonist using two medicinal chemistry transformations (M3/NRI selectivity of >1000). Conjugation to a β(2) agonist motif furnished a molecule with ba...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 54; no. 19; p. 6998
Main Authors: Osborne, Rachel, Clarke, Nick, Glossop, Paul, Kenyon, Amy, Liu, Hao, Patel, Sheena, Summerhill, Susan, Jones, Lyn H
Format: Journal Article
Language:English
Published: United States 13.10.2011
Subjects:
Adrenergic beta-2 Receptor Agonists - chemical synthesis
Adrenergic beta-2 Receptor Agonists - chemistry
Adrenergic beta-2 Receptor Agonists - pharmacology
Adrenergic Uptake Inhibitors - chemical synthesis
Adrenergic Uptake Inhibitors - chemistry
Adrenergic Uptake Inhibitors - pharmacology
Animals
Bronchoconstriction - drug effects
Bronchodilator Agents - chemical synthesis
Bronchodilator Agents - chemistry
Bronchodilator Agents - pharmacology
Caco-2 Cells
Cell Membrane Permeability
Guinea Pigs
Humans
In Vitro Techniques
Microsomes, Liver - metabolism
Models, Molecular
Muscarinic Antagonists - chemical synthesis
Muscarinic Antagonists - chemistry
Muscarinic Antagonists - pharmacology
Pulmonary Disease, Chronic Obstructive - drug therapy
Receptor, Muscarinic M3 - physiology
Structure-Activity Relationship
Trachea - drug effects
Trachea - physiopathology
ISSN:1520-4804, 1520-4804
Online Access:Get more information
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Summary:Following interrogation of a wide-ligand profile database, a nonselective norepinephrin reuptake inhibitor was converted into a novel muscarinic antagonist using two medicinal chemistry transformations (M3/NRI selectivity of >1000). Conjugation to a β(2) agonist motif furnished a molecule with balanced dual pharmacology, as demonstrated in a guinea pig trachea tissue model of bronchoconstriction. This approach provides new starting points for the treatment of chronic obstructive pulmonary disease and illustrates the potential for building selectivity into GPCR modulators that possess intrinsic promiscuity or reverse selectivity.
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ISSN:1520-4804
1520-4804
DOI:10.1021/jm2007535