Preparation and optimization of pyrazolo[1,5-a]pyrimidines as new potent PDE4 inhibitors

Bioorg Med Chem Lett. 2016 Jan 15;26(2):454-459. doi: 10.1016/j.bmcl.2015.11.093. Epub 2015 Nov 26.

Abstract

A new series of pyrazolo[1,5-a]pyrimidines exemplified by compound 1, has been identified with moderate activity (IC50=165nM), following GSK256066 rescaffolding. Compound 1 optimization at positions 2, 3, 6 and 7 gave compound 10 with high in vitro activity (IC50=0.7nM). Modeling studies based on the PDB structure 3GWT with compound 5 showed the expected overlay with the carboxamide, the aryl moiety and the sulfone. Cyclisation of the primary amide to the 5 position of the pyrazolo[1,5-a]pyrimidines scaffold afforded compounds 15 and 16 with 200-fold enhancement in activity and cellular potency.

Keywords: Carboxamide; PDE4 inhibitor; cAMP.

MeSH terms

  • Aminoquinolines / chemistry
  • Cell Line, Tumor
  • Cyclic AMP / biosynthesis
  • Humans
  • Models, Molecular
  • Phosphodiesterase 4 Inhibitors / chemical synthesis
  • Phosphodiesterase 4 Inhibitors / pharmacology*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacology*
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis
  • Sulfones / chemistry
  • Sulfones / pharmacology

Substances

  • 6-((3-((dimethylamino)carbonyl)phenyl)sulfonyl)-8-methyl-4-((3-methyloxyphenyl)amino)-3-quinolinecarboxamide
  • Aminoquinolines
  • Phosphodiesterase 4 Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Sulfones
  • Cyclic AMP