Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors

Amit S. Kalgutkar, Alan B. Marnett, Brenda C. Crews, Rory P Remmel, Lawrence J. Marnett

Research output: Contribution to journalArticle

308 Citations (Scopus)

Abstract

Recent studies from our laboratory have shown that derivatization of the carboxylate moiety in substrate analogue inhibitors, such as 5,8,11,14- eicosatetraynoic acid, and in nonsteroidal antiinflammatory drugs (NSAIDs), such as indomethacin and meclofenamic acid, results in the generation of potent and selective cyclooxygenase-2 (COX-2) inhibitors (Kalgutkar et al. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 925-930). This paper summarizes details of the structure-activity studies involved in the transformation of the arylacetic acid NSAID, indomethacin, into a COX-2-selective inhibitor. Many of the structurally diverse indomethacin esters and amides inhibited purified human COX-2 with IC50 values in the low-nanomolar range but did not inhibit ovine COX-1 activity at concentrations as high as 66 μM. Primary and secondary amide analogues of indomethacin were more potent as COX-2 inhibitors than the corresponding tertiary amides. Replacement of the 4- chlorobenzoyl group in indomethacin esters or amides with the 4-bromobenzyl functionality or hydrogen afforded inactive compounds. Likewise, exchanging the 2-methyl group on the indole ring in the ester and amide series with a hydrogen also generated inactive compounds. Inhibition kinetics revealed that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Conversion of indomethacin into ester and amide derivatives provides a facile strategy for generating highly selective COX-2 inhibitors and eliminating the gastrointestinal side effects of the parent compound.

Original languageEnglish (US)
Pages (from-to)2860-2870
Number of pages11
JournalJournal of Medicinal Chemistry
Volume43
Issue number15
DOIs
StatePublished - Jul 27 2000

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Cyclooxygenase 2 Inhibitors
Amides
Indomethacin
Esters
Anti-Inflammatory Agents
Derivatives
Pharmaceutical Preparations
Cyclooxygenase 2
Hydrogen
5,8,11,14-Eicosatetraynoic Acid
Meclofenamic Acid
Inhibitory Concentration 50
Sheep
Kinetics
Acids
Substrates

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Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. / Kalgutkar, Amit S.; Marnett, Alan B.; Crews, Brenda C.; Remmel, Rory P; Marnett, Lawrence J.

In: Journal of Medicinal Chemistry, Vol. 43, No. 15, 27.07.2000, p. 2860-2870.

Research output: Contribution to journalArticle

Kalgutkar, Amit S. ; Marnett, Alan B. ; Crews, Brenda C. ; Remmel, Rory P ; Marnett, Lawrence J. / Ester and amide derivatives of the nonsteroidal antiinflammatory drug, indomethacin, as selective cyclooxygenase-2 inhibitors. In: Journal of Medicinal Chemistry. 2000 ; Vol. 43, No. 15. pp. 2860-2870.
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