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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Vydané v:	Journal of medicinal chemistry Ročník 54; číslo 19; s. 6998
Hlavní autori:	Osborne, Rachel, Clarke, Nick, Glossop, Paul, Kenyon, Amy, Liu, Hao, Patel, Sheena, Summerhill, Susan, Jones, Lyn H
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 13.10.2011
Predmet:	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
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Shrnutí:	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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1520-4804 1520-4804
DOI:	10.1021/jm2007535