Indolyl esters and amides related to indomethacin are selective COX-2 inhibitors.

Kalgutkar AS, Crews BC, Saleh S, Prudhomme D, Marnett LJ
Bioorg Med Chem. 2005 13 (24): 6810-22

PMID: 16169736 · DOI:10.1016/j.bmc.2005.07.073

Previous studies from our laboratory have revealed that esterification/amidation of the carboxylic acid moiety in the nonsteroidal anti-inflammatory drug, indomethacin, generates potent and selective COX-2 inhibitors. In the present study, a series of reverse ester/amide derivatives were synthesized and evaluated as selective COX-2 inhibitors. Most of the reverse esters/amides displayed time-dependent COX-2 inhibition with IC50 values in the low nanomolar range. Replacement of the 4-chlorobenzoyl group on the indole nitrogen with a 4-bromobenzyl moiety resulted in compounds that retained selective COX-2 inhibitory potency. In addition to inhibiting COX-2 activity in vitro, the reverse esters/amides also inhibited COX-2 activity in the mouse macrophage-like cell line, RAW264.7. Overall, this strategy broadens the scope of our previous methodology of neutralizing the carboxylic acid group in NSAIDs as a means of generating COX-2-selective inhibitors and is potentially applicable to other NSAIDs.

MeSH Terms (12)

Amides Animals Cell Line Cyclooxygenase 2 Cyclooxygenase Inhibitors Esters Humans Indoles Indomethacin Inhibitory Concentration 50 Mice Structure-Activity Relationship

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