Inhalation by design: novel tertiary amine muscarinic M₃ receptor antagonists with slow off-rate binding kinetics for inhaled once-daily treatment of chronic obstructive pulmonary disease

J Med Chem. 2011 Oct 13;54(19):6888-904. doi: 10.1021/jm200884j. Epub 2011 Sep 20.

Abstract

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.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Administration, Inhalation
  • Animals
  • Azetidines / chemical synthesis*
  • Azetidines / chemistry
  • Azetidines / pharmacology
  • Bronchodilator Agents / chemical synthesis*
  • Bronchodilator Agents / chemistry
  • Bronchodilator Agents / pharmacology
  • CHO Cells
  • Cell Line
  • Cell Membrane Permeability
  • Cricetinae
  • Cricetulus
  • Diphenylacetic Acids / chemical synthesis*
  • Diphenylacetic Acids / chemistry
  • Diphenylacetic Acids / pharmacology
  • Dogs
  • Female
  • Guinea Pigs
  • Hepatocytes / metabolism
  • Humans
  • In Vitro Techniques
  • Kinetics
  • Male
  • Microsomes, Liver / metabolism
  • Muscle Relaxation / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Radioligand Assay
  • Rats
  • Receptor, Muscarinic M3 / antagonists & inhibitors*
  • Receptor, Muscarinic M3 / metabolism
  • Recombinant Proteins / antagonists & inhibitors
  • Recombinant Proteins / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Trachea / drug effects
  • Trachea / physiology

Substances

  • 5-(3-(3-hydroxyphenoxy)azetidin-1-yl)-5-methyl-2,2-diphenylhexanamide
  • Azetidines
  • Bronchodilator Agents
  • Diphenylacetic Acids
  • Receptor, Muscarinic M3
  • Recombinant Proteins