ABSTRACT
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.
Subject(s)
Amides/chemistry , Muscarinic Antagonists/chemistry , Quaternary Ammonium Compounds/chemistry , Quinuclidines/chemistry , Receptor, Muscarinic M3/antagonists & inhibitors , Amides/chemical synthesis , 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/pharmacokinetics , Protein Binding , Protein Structure, Tertiary , Rats , Receptor, Muscarinic M3/metabolism , Structure-Activity RelationshipABSTRACT
Novel quaternary ammonium derivatives of N,N-disubstituted (3R)-quinuclidinyl carbamates have been identified as potent M(3) muscarinic antagonists with long duration of action in an in vivo model of bronchoconstriction. These compounds have also presented a high level of metabolic transformation (human liver microsomes). The synthesis, structure-activity relationships and biological evaluation of these compounds are reported.
Subject(s)
Carbamates/chemical synthesis , Carbamates/pharmacology , Drug Discovery , Microsomes, Liver/drug effects , Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/pharmacology , Carbamates/chemistry , Humans , Inhibitory Concentration 50 , Microsomes, Liver/metabolism , Molecular Structure , Muscarinic Antagonists/chemistry , Quaternary Ammonium Compounds/chemical synthesis , Quaternary Ammonium Compounds/chemistry , Quaternary Ammonium Compounds/pharmacology , Quinuclidines/chemical synthesis , Quinuclidines/chemistry , Quinuclidines/pharmacology , Time FactorsABSTRACT
The objective of this work was to discover a novel, long-acting muscarinic M(3) antagonist for the inhaled treatment of chronic obstructive pulmonary disease (COPD), with a potentially improved risk-benefit profile compared with current antimuscarinic agents. A series of novel quaternary ammonium derivatives of (3R)-quinuclidinol esters were synthesized and evaluated. On the basis of its overall profile, (3R)-3-{[hydroxy(di-2-thienyl)acetyl]oxy}-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (aclidinium bromide) emerged as a candidate for once-daily maintenance treatment of COPD. This compound is a potent muscarinic antagonist, with long duration of action in vivo, and was found to have a rapid hydrolysis in human plasma, minimizing the potential to induce class-related systemic side effects. Aclidinium bromide is currently in phase III development for maintenance treatment of patients with COPD.