NO-NSAIDs: Gastric-sparing nitric oxide-releasable prodrugs of non-steroidal anti-inflammatory drugs

Gastric-sparing NO-NSAIDs were designed, synthesized and evaluated. Among those evaluated, NO-Diclofenac ( 2b) has shown excellent bioavailability, anti-inflammatory activity, NO-releasing profile and gastric-sparing properties . Recently, a new class of nitric-oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) is being studied as ‘Safe NSAIDs’ because of their gastric-sparing properties. As an extension of our novel disulfide linker technology, we have designed, synthesized and evaluated novel NO-releasing NSAID prodrugs such as NO-Aspirin ( 1b– d) and NO-Diclofenac ( 2b– c). Although the amide-containing derivative 1d did not show any bioavailability, the remaining compounds have shown fair to excellent pharmacokinetic, anti-inflammatory and gastric-sparing properties. Among them, however, the NO-Diclofenac ( 2b) has shown the most promising pharmacokinetic, anti-inflammatory and NO-releasing properties and protected rats from NSAID-induced gastric damage which could be attributable to the beneficial effects of NO released from these prodrugs.