Structural modification of indomethacin toward selective inhibition of COX-2 with a significant increase in van der Waals contributions

• Published in: Bioorganic & medicinal chemistry 2019-05, Vol.27 (9), p.1789-1794
• Main Authors: Ikeda, Akari, Funakoshi, Eishi, Araki, Mitsugu, Ma, Biao, Karuo, Yukiko, Tarui, Atsushi, Sato, Kazuyuki, Okuno, Yasushi, Kawai, Kentaro, Omote, Masaaki
• Format: Article
• Language: English
• Subjects: (E)-trimethyl (3,3,3-trifluoroprop-1-enyl)silane; 3,3,3-Trifluoroprop-1-enyl group; Binding Sites; COX-2 selective inhibition; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - chemistry; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - metabolism; Indomethacin; Indomethacin - chemistry; Indomethacin - metabolism; Molecular Dynamics Simulation; Protein Structure, Tertiary; Static Electricity; van der Waals contribution
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2019.03.021

[Display omitted] We have synthesized a fluorinated analogue of indomethacin bearing a 3,3,3-trifluoroprop-1-enyl group at its 2-position and evaluated its inhibitory activity towards the COX-1 and COX-2 enzymes in vitro. The results revealed that this fluorinated analogue exhibited much greater inhibitory activity and selectivity towards COX-2 than indomethacin. The increased affinity between the fluorinated analogue and COX-2 was attributed to a significant increase in van der Waals contacts (i.e. van der Waals contributions in ΔG were −13.80 kcal/mol for COX-1 and −18.46 kcal/mol for COX-2), explaining an effect of the fluorine substituent in enzyme selectivity. This newly synthesized fluorinated analogue therefore represents a potent and selective COX-2 inhibitor.