Some cyclooxygenase (COX)‐2 selective medications were withdrawn from the
market just a few years after their production due to cardiovascular side effects. In
this study, a new series of pyrimidine/thiazole hybrids 7a–p was synthesized as
selective COX‐2/soluble epoxide hydrolase (sEH) inhibitors with analgesic and antiinflammatory
effects, and lower cardiotoxicity effects. The target compounds were
synthesized and in vitro tested against COX‐1, COX‐2, and sEH enzymes. Hybrids 7j,
7k, and 7i showed the greatest COX‐2‐inhibitory activity and were discovered to be
the most potent dual COX‐2/sEH inhibitors. In vivo tests revealed that these hybrids
were the most active analgesic/anti‐inflammatory agents, with improved ulcerogenic
and cardioprotective properties. Finally, the most active dual inhibitors were docked
into COX‐2/sEH active regions to explain their binding mechanisms.