Uk. Bandarage et al., Nitrosothiol esters of diclofenac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs, J MED CHEM, 43(21), 2000, pp. 4005-4016
Despite its widespread use, diclofenac has gastrointestinal liabilities com
mon to nonsteroidal antiinflammatory drugs (NSAIDs) that might be reduced b
y concomitant administration of a gastrointestinal cytoprotectant such as n
itric oxide (NO). A series of novel diclofenac esters containing a nitrosot
hiol (-S-NO) moiety as a NO donor functionality has been synthesized and ev
aluated in vivo for bioavailability, pharmacological activity, and gastric
irritation. All S-NO-diclofenac derivatives acted as orally bioavailable pr
odrugs, producing significant levels of diclofenac in plasma within 15 min
after oral administration to mice. At equimolar oral doses, S-NO-diclofenac
derivatives (20a-21b) displayed rat antiinflammatory and analgesic activit
ies comparable to those of diclofenac in the carrageenan-induced paw edema
test and the mouse phenylbenzoquinone-induced writhing test, respectively.
All tested S-NO-diclofenac derivatives (20a-21b) were gastric-sparing in th
at they elicited markedly fewer stomach lesions as compared to the stomach
lesions caused by a high equimolar dose of diclofenac in the rat. Nitrosoth
iol esters of diclofenac comprise a novel class of NO-donating compounds ha
ving therapeutic potential as nonsteroidal antiinflammatory agents with an
enhanced gastric safety profile.