Synthesis and biological activity of pyrido[3',2':4,5]furo[3,2-d]pyrimidine derivatives as novel and potent phosphodiesterase type 4 inhibitors

Eur J Med Chem. 2011 Oct;46(10):4946-56. doi: 10.1016/j.ejmech.2011.07.054. Epub 2011 Aug 5.

Abstract

A series of pyrido[3',2':4,5]furo[3,2-d]pyrimidines (PFP) were synthesized and tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, is presented. Both gem-dimethylcyclohexyl moieties fused to the pyridine ring and the substitution at the 5 position of the PFP scaffold, proved to be key elements in order to get a high affinity in the enzyme.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / drug therapy
  • Asthma / enzymology
  • Caco-2 Cells
  • Cell Membrane Permeability
  • Cyclic Nucleotide Phosphodiesterases, Type 4 / metabolism*
  • Ferrets
  • Humans
  • Models, Molecular
  • Phosphodiesterase 4 Inhibitors / chemical synthesis
  • Phosphodiesterase 4 Inhibitors / chemistry*
  • Phosphodiesterase 4 Inhibitors / pharmacokinetics
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Pulmonary Disease, Chronic Obstructive / drug therapy
  • Pulmonary Disease, Chronic Obstructive / enzymology
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacokinetics
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Phosphodiesterase 4 Inhibitors
  • Pyrimidines
  • Cyclic Nucleotide Phosphodiesterases, Type 4