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

NO-NSAIDs. Part 3: Nitric Oxide-Releasing Prodrugs of Non-steroidal Anti-inflammatory Drugs

“…As proposed earlier, the disulfide group plays a prominent role in the mechanism of release of NO from these compounds. 8,23) NO-NSAID Synthesis General methods used for the synthesis of NO-NSAIDs 9-33 are outlined in Chart 1. In general, the desired NO-NSAIDs were synthesized from the parent NSAIDs by activation of their carboxylic acid function followed by appendage of appropriate linker intermediates 34-38a and 38b (Fig.…”

“…Thus, the ester-linked NO-NSAIDs 9-16 were synthesized by employing one of the four standard methods of carboxylic acid activation followed by their reaction with linker intermediate 36 (35 8) NO-aspirin 9 and NO-ibuprofen 15 were synthesized in 45−54% yields by first converting the parent drugs aspirin (1) and ibuprofen (7) into their respective acid chlorides using oxalyl chloride and N,N-dimethylformamide (DMF) method, followed by their reaction with intermediate 36 in the presence of triethylamine. In case of naproxen (3), flurbiprofen (4), ketoprofen (5) and indomethacin (8), they were first converted to their respective imidazolide species using N,N′-carbonyldiimidazole (CDI), followed by their in situ reaction with intermediate 36 to afford 28-67% of the corresponding NO-NSAIDs 11-13 and 16. NO-sulindac 14 was prepared in 53% yield by coupling sulindac (6) directly with intermediate 36 in presence of N,N′-dicyclohexyl carbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP).…”

“…3). This lactam formation was more pronounced when we attempted to synthesize 8) using trifluoroacetic acid. In the second step, the NSAIDs were converted to their respective acid chlorides by treatment with thionyl chloride or oxalyl chloride/ DMF (or imidazolide by the reaction with CDI).…”

“…7) In a recent publication of preliminary results from this study, we reported NO-aspirin and NO-diclofenac as potentially "safe" prodrugs of aspirin (1) and diclofenac (2), respectively. 8) Among the reported NOdiclofenac prodrugs (Fig. 2), the mono ester prodrug 10 had shown excellent oral bioavailability and anti-inflammatory activity comparable to those of diclofenac (2) in rat models.…”

“…Encouraged by the successful identification of a potentially "safe NO-diclofenac" prodrug 10, we have further extended the application of the "SS-nitrate" strategy to explore the possibility of discovering potentially "safe NO-NSAID" prodrugs of other widely used NSAIDs such as naproxen (3), flurbiprofen (4), ketoprofen (5), sulindac (6), ibuprofen (7) and indomethacin (8) (Fig. 2) and the results from those studies are reported in this article.…”