Indomethacin with enhanced selectivity for COX-2
Indomethacin N-octyl amide is a potent and non-selective inhibitor of both COX-1 and COX-2 [1].
Cyclooxygenase (COX) is the key enzyme required for the conversion of arachidonic acid to prostaglandins. Cyclooxygenase enzymes have been involved in diverse physiological situations and disease processes ranging from inflammation to cancer. Until now, two cyclooxygenase isoforms have been identified, COX-1 and COX-2. The COX-1 enzyme is produced constitutively (i.e., gastric mucosa) and COX-2 is inducible (i.e., sites of inflammation) [2].
Indomethacin is a potent but non-selective inhibitor of both COX-1 and COX-2. Indomethacin is a substituted indole acetic acid, wherein the carboxylate can be derivitized as an ester or amide. Conversion of indomethacin into ester and amide derivatives provides a facile strategy for generating highly selective COX-2 inhibitors. Indomethacin N-octyl amide inhibited the activity of ovine COX-1 and human recombinant COX-2 with the IC50 values of 66 μM and 40 nM, respectively. While the IC50 of indomethacin for the inhibition of COX-1 and COX-2 were 0.67 μM and 0.05 μM, respectively [1].
参考文献:
[1] Kalgutkar A S, Marnett A B, Crews B C, et al.? Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors[J]. Journal of medicinal chemistry, 2000, 43(15): 2860-2870.
[2] Dubois R N, Abramson S B, Crofford L, et al.? Cyclooxygenase in biology and disease[J]. The FASEB journal, 1998, 12(12): 1063-1073.
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