Design, synthesis and evaluation of dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors

Bioorg Med Chem Lett. 2014 Jan 1;24(1):249-53. doi: 10.1016/j.bmcl.2013.11.028. Epub 2013 Nov 21.

Abstract

A novel series of formoterol-phthalazinone hybrids were synthesised and evaluated as dual pharmacology β2-adrenoceptor agonists and PDE4 inhibitors. Most of the hybrids displayed high β2-adrenoceptor agonist and moderate PDE4 inhibitory activities. The most potent compound, (R,R)-11c, exhibited agonist (EC50=1.05nM, pEC50=9.0) and potent PDE4B2 inhibitory activities (IC50=0.092μM).

Keywords: Bronchodilator; Chronic obstructive pulmonary disease (COPD); PDE4 inhibitor; β(2)-Adrenoceptor agonist.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Agonists / chemical synthesis
  • Adrenergic beta-2 Receptor Agonists / chemistry
  • Adrenergic beta-2 Receptor Agonists / pharmacology*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Ethanolamines / chemical synthesis
  • Ethanolamines / chemistry
  • Ethanolamines / pharmacology*
  • Formoterol Fumarate
  • Humans
  • Molecular Structure
  • Phosphodiesterase 4 Inhibitors / chemical synthesis
  • Phosphodiesterase 4 Inhibitors / chemistry
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Phthalazines / chemical synthesis
  • Phthalazines / chemistry
  • Phthalazines / pharmacology*
  • Receptors, Adrenergic, beta-2 / metabolism
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • Adrenergic beta-2 Receptor Agonists
  • Ethanolamines
  • Phosphodiesterase 4 Inhibitors
  • Phthalazines
  • Receptors, Adrenergic, beta-2
  • Recombinant Proteins
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Formoterol Fumarate