A new pyrazolo pyrimidine derivative inhibitor of cyclooxygenase-2 with anti-angiogenic activity.
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.
Devesa
Isabel
I
Departamento de Farmacología, Universidad de Valencia, 46100 Burjasot, Valencia, Spain.
Alcaraz
M José
MJ
Riguera
Ricardo
R
Ferrándiz
M Luisa
ML
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002351:Carrageenan; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D005260:Female; D006099:Granuloma / Q000139:chemically induced / Q000473:pathology; D007375:Interleukin-1 / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000517:prevention & control; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015054:Zymosan
D020533:Angiogenesis Inhibitors; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; C493309:N(4)-benzyl-N(6),N(6)-dimethyl-1-1(tert-butyl)-1H-pyrazolo(3,4-d)pyrimidine-6,4-diamine; D009578:Nitrobenzenes; D011720:Pyrazoles; D011743:Pyrimidines; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D002351:Carrageenan; D015054:Zymosan; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone