4-Methyl-3-(arylsulfonyl)furoxans: a new class of potent inhibitors of platelet aggregation.
A series of 4-methyl-3-(arylthio)furoxans were synthesized by oxidation of 1-(arylthio)-2-methylglyoxymes with dinitrogen tetroxide. Reduction with trimethyl phosphite of the furoxan derivatives afforded the corresponding furazans, while oxidation with an equimolar amount of 30% hydrogen peroxide in acetic acid or with an excess of 81% hydrogen peroxide in trifluoroacetic acid afforded the corresponding arylsulfinyl and arylsulfonyl analogues, respectively. All the furoxan and furazan derivatives showed activity as inhibitors of platelet aggregation. 4-Methyl-3-(arylsulfonyl)furoxans were the most potent derivatives of the series. 4-Methyl-3-(phenylsulfonyl)furoxan (10a), one of the most active derivatives, inhibits the AA-induced increase of cytosolic free Ca2+ and production of malondialdehyde. A primary action of the compound on cyclooxygenase is excluded, as a stable epoxymethano analogue of prostaglandin H2 does not reverse the inhibitory effect of 10a. This compound produces a significant increase in cGMP which is likely to cause inhibition at an early stage of the platelet activation pathway.
Calvino
R
R
Dipartimento di Scienza e Tecnologia del Farmaco, Università di Torino, Italy.
Fruttero
R
R
Ghigo
D
D
Bosia
A
A
Pescarmona
G P
GP
Gasco
A
A
D016718:Arachidonic Acid / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D006801:Humans; D008315:Malondialdehyde / Q000097:blood; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D010069:Oxadiazoles; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; C074047:4-methyl-3-(phenylsulfonyl)furoxan; D008315:Malondialdehyde; D006152:Cyclic GMP; D002118:Calcium