Synthesis of 1,5-diarylpyrazol-3-propanoic acids towards inhibition of cyclooxygenase-1/2 activity and 5-lipoxygenase-mediated LTB4 formation.
A set of 25 derivatives of 3-[1-(6-substituted-pyridazin-3-yl)-5-(4-substituted-phenyl)-1H-pyrazol-3-yl]propanoic acids has been synthesized and evaluated for their in vitro cyclooxygenase-1/2 (COX-1/ 2) inhibitory activity using assays with purified COX-1 and COX-2 enzymes as well as for their 5-lipoxygenase (5-LO)-mediated LTB4 formation inhibitory activity using an assay with activated human polymorphonuclear leukocytes (PMNL). Among the synthesized compounds, especially 4g showed COX-1 (IC50 = 1.5 microM) and COX-2 (IC50 = 1.6 microM) inhibitory activity, whereas compounds 4 b and 4 f resulted in the inhibition of 5-LO-mediated LTB4 formation at 14 microM and 12 microM IC50 values, respectively, without any significant inhibition on COX isoforms.
Ergün
Burcu Calişkan Ergün
BC
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, Ankara, Turkey.
Nuñez
Maria Teresa
MT
Labeaga
Luis
L
Ledo
Francisco
F
Darlington
Janice
J
Bain
Gretchen
G
Cakir
Bilge
B
Banoglu
Erden
E
D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D011422:Propionates / Q000138:chemical synthesis* / Q000494:pharmacology*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D016859:Lipoxygenase Inhibitors; D011422:Propionates; D011720:Pyrazoles; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2