title: Indolyl esters and amides related to indomethacin are selective COX-2 inhibitors.
abstract: 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.
authors.affiliation: A.B. Hancock, Jr., Memorial Laboratory for Cancer Research, Department of Biochemistry and Chemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232-0146, USA.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Kalgutkar
authors.forename: Brenda C
authors.initials: BC
authors.lastname: Crews
authors.forename: Sam
authors.initials: S
authors.lastname: Saleh
authors.forename: Daniel
authors.initials: D
authors.lastname: Prudhomme
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D007213:Indomethacin / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D051379:Mice; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D016861:Cyclooxygenase Inhibitors; D004952:Esters; D007211:Indoles; C030374:indole; D051546:Cyclooxygenase 2; D007213:Indomethacin