Background: Improving the gastrointestinal safety profile of Non-Steroidal Anti-
Inflammatory Drugs (NSAIDs) is an important goal. An important strategy to develop NSAIDs
with minimal Gastrointestinal (GI) toxicity is to target the COX-2 isoform with a selective inhibitor.
Methods: In this study we selected ketoprofen as a lead NSAID for development into safer agents.
1, 2, 4-Oxadiazole moiety was employed to mask the free acid group of the ketoprofen to get six
different derivatives hypothesized to have minimal GI irritation. In Vivo anti-inflammatory and
analgesic activities of these six synthesized derivatives were tested and compared to equivalent dose
of the parent drug.
Results: Three compounds showed superior anti-inflammatory activity (76.29%, 80.45% &79.06%
inhibition) compared to the parent drug (72.71% inhibition), in a carrageenan induced paw edema
model (peak at 4h). One compound, 3d also showed moderate analgesic activity (51.14%), in comparison
to ketoprofen (63.97%) in an acetic acid induced writhing model. In addition, the tested
compounds were found to possess much less degree of ulcerogenic potential (almost half) compared
to the parent NSAID, ketoprofen. Their unique selectivity toward the COX-2 enzyme was investigated
using molecular modeling techniques.
Conclusion: Results of compound 3d which showed highest anti-inflammatory and analgesic activities
with much reduced ulcerogenic potential, are highly encouraging and may serve as new
COX-2 selective lead and merits further investigation.