Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating metabolic inactivation: an antedrug approach

J Med Chem. 2010 Jun 10;53(11):4522-30. doi: 10.1021/jm100326d.

Abstract

A series of saligenin beta(2) adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection. The compounds were screened for beta(2), beta(1), and beta(3) agonist activity in CHO cells. The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea. Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized. Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration. A proposed binding mode for 13f to the beta(2)-receptor is presented.

MeSH terms

  • Adrenergic beta-2 Receptor Agonists*
  • Adrenergic beta-Agonists / chemical synthesis
  • Adrenergic beta-Agonists / chemistry*
  • Adrenergic beta-Agonists / metabolism
  • Adrenergic beta-Agonists / pharmacology*
  • Animals
  • Benzyl Alcohol / chemistry
  • Benzyl Alcohols / chemical synthesis
  • Benzyl Alcohols / chemistry
  • Benzyl Alcohols / metabolism
  • Benzyl Alcohols / pharmacology
  • CHO Cells
  • Chlorobenzenes / chemical synthesis
  • Chlorobenzenes / chemistry
  • Chlorobenzenes / metabolism
  • Chlorobenzenes / pharmacology
  • Cricetinae
  • Cricetulus
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Rats
  • Receptors, Adrenergic, beta-2 / chemistry
  • Structure-Activity Relationship

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Adrenergic beta-Agonists
  • Benzyl Alcohols
  • Chlorobenzenes
  • Receptors, Adrenergic, beta-2
  • vilanterol
  • Benzyl Alcohol