GSK256066, an exceptionally high-affinity and selective inhibitor of phosphodiesterase 4 suitable for administration by inhalation: in vitro, kinetic, and in vivo characterization

J Pharmacol Exp Ther. 2011 Apr;337(1):145-54. doi: 10.1124/jpet.110.173690. Epub 2011 Jan 4.


Oral phosphodiesterase (PDE) 4 inhibitors such as roflumilast have established the potential of PDE4 inhibition for the treatment of respiratory diseases. However, PDE4 inhibitor efficacy is limited by mechanism-related side effects such as emesis and nausea. Delivering the inhibitor by the inhaled route may improve therapeutic index, and we describe 6-({3-[(dimethylamino)carbonyl]phenyl}sulfonyl)-8-methyl-4-{[3-methyloxy) phenyl]amino}-3-quinolinecarboxamide (GSK256066), an exceptionally high-affinity inhibitor of PDE4 designed for inhaled administration. GSK256066 is a slow and tight binding inhibitor of PDE4B (apparent IC(50) 3.2 pM; steady-state IC(50) <0.5 pM), which is more potent than any previously documented compound, for example, roflumilast (IC(50) 390 pM), tofimilast (IC(50) 1.6 nM), and cilomilast (IC(50) 74 nM). Consistent with this, GSK256066 inhibited tumor necrosis factor α production by lipopolysaccharide (LPS)-stimulated human peripheral blood monocytes with 0.01 nM IC(50) (compared with IC(50) values of 5, 22, and 389 nM for roflumilast, tofimilast, and cilomilast, respectively) and by LPS-stimulated whole blood with 126 pM IC(50). GSK256066 was highly selective for PDE4 (>380,000-fold versus PDE1, PDE2, PDE3, PDE5, and PDE6 and >2500-fold against PDE7), inhibited PDE4 isoforms A-D with equal affinity, and had a substantial high-affinity rolipram binding site ratio (>17). When administered intratracheally to rats, GSK256066 inhibited LPS-induced pulmonary neutrophilia with ED(50) values of 1.1 μg/kg (aqueous suspension) and 2.9 μg/kg (dry powder formulation) and was more potent than an aqueous suspension of the corticosteroid fluticasone propionate (ED(50) 9.3 μg/kg). Thus, GSK256066 has been demonstrated to have exceptional potency in vitro and in vivo and is being clinically investigated as a treatment for chronic obstructive pulmonary disease.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Inhalation
  • Aminoquinolines / administration & dosage*
  • Aminoquinolines / metabolism
  • Aminoquinolines / pharmacokinetics
  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / pharmacokinetics
  • Dose-Response Relationship, Drug
  • Humans
  • Leukocytes, Mononuclear / drug effects
  • Leukocytes, Mononuclear / enzymology
  • Phosphodiesterase 4 Inhibitors / administration & dosage*
  • Phosphodiesterase 4 Inhibitors / metabolism
  • Phosphodiesterase 4 Inhibitors / pharmacokinetics
  • Protein Binding / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Sulfones / administration & dosage*
  • Sulfones / metabolism
  • Sulfones / pharmacokinetics


  • 6-((3-((dimethylamino)carbonyl)phenyl)sulfonyl)-8-methyl-4-((3-methyloxyphenyl)amino)-3-quinolinecarboxamide
  • Aminoquinolines
  • Phosphodiesterase 4 Inhibitors
  • Sulfones
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4B protein, human