Identification of the 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives as highly selective PDE4B inhibitors

Bioorg Med Chem Lett. 2014 Feb 1;24(3):893-9. doi: 10.1016/j.bmcl.2013.12.076. Epub 2013 Dec 25.

Abstract

A PDE4B subtype selective inhibitor is expected to have a wider therapeutic window than non-selective PDE4 inhibitors. In this Letter, two series of 7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives and 5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivatives were evaluated for their PDE4B subtype selectivity using human PDE4B2 and PDE4D2 full length enzymes. To improve their PDE4B selectivity over PDE4D, we optimized the substituents on the pyrimidine ring and the side chain phenyl ring, resulting in several derivatives with more than 100-fold selectivity for PDE4B. Consequently, we identified 2-(3-chloro-4-methoxy-phenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine derivative 54 as a highly selective PDE4B inhibitor, which had potent hPDE4B inhibitory activity with an IC50 value of 3.0 nM and 433-fold PDE4B selectivity over PDE4D.

Keywords: COPD; Full length; PDE4; PDE4B; PDE4D; Selective inhibitor.

MeSH terms

  • Binding Sites
  • Cyclic S-Oxides / chemistry*
  • Cyclic S-Oxides / isolation & purification
  • Cyclic S-Oxides / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Phenylacetates / chemistry*
  • Phenylacetates / isolation & purification
  • Phenylacetates / pharmacology*
  • Phosphodiesterase 4 Inhibitors / chemistry*
  • Phosphodiesterase 4 Inhibitors / isolation & purification
  • Phosphodiesterase 4 Inhibitors / pharmacology*

Substances

  • 2-(4-((2-(3-chloro-4-methoxyphenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano(3,2-d)pyrimidin-4-yl)amino)-2-fluorophenyl)acetic acid
  • Cyclic S-Oxides
  • Enzyme Inhibitors
  • Phenylacetates
  • Phosphodiesterase 4 Inhibitors