Nitrosothiol esters of diclofenac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs

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.