Substituted pyrazolylhydrazones: a new class of platelet aggregation inhibitors.
A series of 5-pyrazolylhydrazone derivatives (I) were designed to be mixed hybrid isosteres of both BW-755C and CBS-1108 which belong to the class of dual cyclooxygenase and 5-lipoxygenase inhibitors. Pharmacological evaluation of some members of this series (Ia, 1-formyl-3,4-methylenedioxy-6-nitrobenzene-5-(1-phenyl-3-methyl-4-nit ropyrazolyl)hydrazone; Ib, 2-formylfurane-5-(1-phenyl-3-methyl-4-nitropyrazolyl)hydr azo ne;Ic, (E)-2-(formylethenylfurane)-5-(1-phenyl-3-methyl-4-nitropyrazol yl)hydrazone showed that they inhibit the in vitro platelet aggregation of citrated platelet-rich rabbit plasma induced by ADP (5 microM), collagen (5 micrograms/ml) and arachidonic acid (100 microM). Compounds Ia and Ic at 100 microM concentration showed 49% and 58% inhibition, respectively, of ADP-induced aggregation. In the arachidonic acid-induced aggregation, compounds Ia and Ib at 100 microM concentration fully inhibited platelet aggregation. All compounds significantly inhibited the collagen-induced aggregation. In contrast, indomethacin (10 microM) showed 100% and 85% aggregation inhibition against arachidonic acid and collagen, respectively, and was inactive in the ADP-induced aggregation test. These results suggest that the structure-activity relationship in this series of compounds is dependent on the hydrazone moiety at position 5 of the pyrazole ring and on the distance between the aryl ring and the pyrazole ring and that the 2-furyl ring is at the optimal distance for the maximal activity.
Silveira
I A
IA
Departamento de Farmacologia Básica e Clínica, Universidade Federal do Rio de Janeiro, Brasil.
Paulo
L G
LG
Miranda
A L
AL
Rocha
S O
SO
Freitas
A C
AC
Barreiro
E J
EJ
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine / Q000737:chemistry; D000447:Aldehydes / Q000737:chemistry; D006835:Hydrazones / Q000737:chemistry*; D066298:In Vitro Techniques; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry*; D011720:Pyrazoles / Q000737:chemistry; D013329:Structure-Activity Relationship
D000447:Aldehydes; D006835:Hydrazones; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine