Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides as potent and long acting muscarinic antagonists

Novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides have been identified as potent M3 muscarinic antagonists with a long duration of action in an in vivo model of bronchoconstriction. The synthesis, structure-activity relationships and biological evaluation of this series of compounds...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2015-04, Vol.25 (8), p.1736-1741
Main Authors: Prat, Maria, Buil, María Antonia, Fernández, Maria Dolors, Tort, Laia, Monleón, Juan Manuel, Casals, Gaspar, Ferrer, Manuel, Castro, Jordi, Gavaldà, Amadeu, Miralpeix, Montserrat, Ramos, Israel, Vilella, Dolors, Huerta, Josep Maria, Espinosa, Sònia, Hernández, Begoña, Segarra, Victor, Córdoba, Mònica
Format: Article
Language:English
Subjects:
Amides - chemical synthesis
Amides - chemistry
Amides - pharmacokinetics
Animals
Binding Sites
Bronchoconstrictor Agents - chemical synthesis
Bronchoconstrictor Agents - chemistry
Bronchoconstrictor Agents - pharmacokinetics
Drug Evaluation, Preclinical
Half-Life
Humans
Hydrogen Bonding
Molecular Docking Simulation
Muscarinic Antagonists - chemical synthesis
Muscarinic Antagonists - chemistry
Muscarinic Antagonists - pharmacokinetics
Protein Binding
Protein Structure, Tertiary
Quaternary Ammonium Compounds - chemistry
Quinuclidines - chemistry
Rats
Receptor, Muscarinic M3 - antagonists & inhibitors
Receptor, Muscarinic M3 - metabolism
Structure-Activity Relationship
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Summary:Novel quaternary ammonium derivatives of (3R)-quinuclidinyl amides have been identified as potent M3 muscarinic antagonists with a long duration of action in an in vivo model of bronchoconstriction. The synthesis, structure-activity relationships and biological evaluation of this series of compounds are reported.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2015.02.065