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    COX-2 selective drugs have been withdrawn from the market due to cardiovascular side effects, just a few years after their discovery. As a result, a new series of 1,5-diaryl pyrazole carboxamides 19-31 was synthesized as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxic properties. The target compounds were synthesized and tested in vitro against COX-1, COX-2, and sEH enzymes. Compounds 20, 22 and 29 exhibited the most substantial COX-2 inhibitory activity (IC50 values: 0.82-1.12 µM) and had SIs of 13, 18, and 16, respectively, (c.f. celecoxib; SI = 8). Moreover, compounds 20, 22, and 29 were the most potent dual COX-2/sEH inhibitors, with IC50 values of 0.95, 0.80, and 0.85 nM against sEH, respectively, and were more potent than the standard AUDA (IC50 = 1.2 nM). Furthermore, in vivo studies revealed that these compounds were the most active as analgesic/anti-inflammatory derivatives with a good cardioprotective profile against cardiac biomarkers and inflammatory cytokines. Finally, the most active dual inhibitors were docked inside COX-2/sEH active sites to explain their binding modes. Copyright © 2021 Elsevier Inc. All rights reserved.


    O M Hendawy, Hesham A M Gomaa, Sami I Alzarea, Mutariah S Alshammari, Fatma A M Mohamed, Yaser A Mostafa, Ahmed H Abdelazeem, Mostafa H Abdelrahman, Laurent Trembleau, Bahaa G M Youssif. Novel 1,5-diaryl pyrazole-3-carboxamides as selective COX-2/sEH inhibitors with analgesic, anti-inflammatory, and lower cardiotoxicity effects. Bioorganic chemistry. 2021 Nov;116:105302

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    PMID: 34464816

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