ipratropium-bromide-anhydrous and Pulmonary-Disease--Chronic-Obstructive

A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.

Topics: Administration, Inhalation; Animals; Azetidines; Bronchodilator Agents; Cell Line; Cell Membrane Permeability; CHO Cells; Cricetinae; Cricetulus; Diphenylacetic Acids; Dogs; Female; Guinea Pigs; Hepatocytes; Humans; In Vitro Techniques; Kinetics; Male; Microsomes, Liver; Muscle Relaxation; Muscle, Smooth; Pulmonary Disease, Chronic Obstructive; Radioligand Assay; Rats; Receptor, Muscarinic M3; Recombinant Proteins; Stereoisomerism; Structure-Activity Relationship; Trachea

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.

Topics: Administration, Inhalation; Animals; Bronchial Spasm; CHO Cells; Cricetinae; Cricetulus; Drug Stability; Esters; Guinea Pigs; Humans; Male; Mice; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quaternary Ammonium Compounds; Quinuclidines; Radioligand Assay; Receptor, Muscarinic M3; Stereoisomerism; Structure-Activity Relationship; Tropanes

SAR around alkyne-quinuclidine derivatives allowed the discovery of highly potent muscarinic antagonists displaying interesting preferential slow off-rates from the M3 receptor.

Topics: Alkynes; Cholinergic Antagonists; Molecular Structure; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Structure-Activity Relationship