A new pyrazolo pyrimidine derivative inhibitor of cyclooxygenase-2 with anti-angiogenic activity

Eur J Pharmacol. 2004 Mar 19;488(1-3):225-30. doi: 10.1016/j.ejphar.2004.02.015.

Abstract

In a previous study, we reported a new pyrazolo pyrimidine derivative, N(4)-benzyl-N(6),N(6)-dimethyl-1-1(tert-butyl)-1H-pyrazolo[3,4-d]pyrimidine-6,4-diamine (DPP), which inhibited potently cyclooxygenase-2 activity in intact cell assays with minor activity against cyclooxygenase-1 (IC(50)=0.9 nM for cyclooxygenase-2 versus IC(50)=59.6 nM for cyclooxygenase-1). In the present work, this behaviour was confirmed in vivo by using the 24-h zymosan-injected mouse air pouch model (ID(50)=1.36 nM/pouch for prostaglandin E(2) level). We also studied the possible beneficial effect of DPP in the angiogenesis-dependent murine air pouch granuloma and rat paw carrageenan-induced hyperalgesia models. DPP exerted analgesic and anti-angiogenic (52% reduction in angiogenesis at 10 mg/kg, i.p.) effects that may be associated with inhibition of cyclooxygenase-2 activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inhibitors / pharmacology*
  • Animals
  • Carrageenan
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • Dinoprostone / metabolism
  • Edema / chemically induced
  • Edema / prevention & control
  • Female
  • Granuloma / chemically induced
  • Granuloma / pathology
  • Interleukin-1 / biosynthesis
  • Isoenzymes / metabolism*
  • Mice
  • Neovascularization, Pathologic / pathology
  • Neovascularization, Pathologic / prevention & control
  • Nitrobenzenes / pharmacology
  • Prostaglandin-Endoperoxide Synthases / metabolism*
  • Pyrazoles / pharmacology*
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Wistar
  • Sulfonamides / pharmacology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Zymosan

Substances

  • Angiogenesis Inhibitors
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Interleukin-1
  • Isoenzymes
  • N(4)-benzyl-N(6),N(6)-dimethyl-1-1(tert-butyl)-1H-pyrazolo(3,4-d)pyrimidine-6,4-diamine
  • Nitrobenzenes
  • Pyrazoles
  • Pyrimidines
  • Sulfonamides
  • Tumor Necrosis Factor-alpha
  • N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide
  • Carrageenan
  • Zymosan
  • Cyclooxygenase 2
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone