In continuation of our efforts to discover novel nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) as potentially “Safe NSAIDs,” we report herein the design, synthesis and evaluation of 21 new NO-NSAIDs of commonly used NSAIDs such as aspirin, diclofenac, naproxen, flurbiprofen, ketoprofen, sulindac, ibuprofen and indomethacin. These prodrugs have NO-releasing disulfide linker attached to a parent NSAID
via linkages such as an ester (compounds
9–
16), a double ester (compounds
17–
24), an imide (compounds
25–
30) or an amide (compounds
31–
33). Among these NO-NSAIDs, the ester-containing NO-aspirin (
9), NO-diclofenac (
10), NO-naproxen (
11), and the imide-containing NO-aspirin (
25), NO-flurbiprofen (
27) and NO-ketoprofen (
28) have shown promising oral absorption, anti-inflammatory activity and NO-releasing property, and also protected rats from NSAID-induced gastric damage. NO-aspirin compound
25, on further co-evaluation with aspirin at equimolar doses, exhibited comparable dose-dependent pharmacokinetics, inhibition of gastric mucosal prostaglandin E
2 (PGE
2) synthesis and analgesic properties to those of aspirin, but retained its gastric-sparing properties even after doubling its oral dose. These promising NO-NSAIDs could therefore represent a new class of potentially “Safe NSAIDs” for the treatment of arthritic pain and inflammation.
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