Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors

Amit S. Kalgutkar, Brenda C. Crews, Scott W. Rowlinson, Alan B. Marnett, Kevin R. Kozak, Rory P. Remmel, Lawrence J. Marnett

Research output: Contribution to journalArticle

227 Citations (Scopus)

Abstract

All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.

Original languageEnglish (US)
Pages (from-to)925-930
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number2
DOIs
StatePublished - Jan 18 2000

Fingerprint

Cyclooxygenase 2 Inhibitors
Amides
Anti-Inflammatory Agents
Indomethacin
5,8,11,14-Eicosatetraynoic Acid
Meclofenamic Acid
Pharmaceutical Preparations
Cyclooxygenase 2
Prostaglandin-Endoperoxide Synthases
Esters
Cyclooxygenase 1
Cyclooxygenase Inhibitors
Non-Steroidal Anti-Inflammatory Agents
Carboxylic Acids
Site-Directed Mutagenesis
Isoenzymes
Cultured Cells
Binding Sites
Inflammation
Enzymes

Cite this

Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors : Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors. / Kalgutkar, Amit S.; Crews, Brenda C.; Rowlinson, Scott W.; Marnett, Alan B.; Kozak, Kevin R.; Remmel, Rory P.; Marnett, Lawrence J.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 2, 18.01.2000, p. 925-930.

Research output: Contribution to journalArticle

@article{578bb95d151346e984a424c8e0a729dc,
title = "Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors",
abstract = "All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.",
author = "Kalgutkar, {Amit S.} and Crews, {Brenda C.} and Rowlinson, {Scott W.} and Marnett, {Alan B.} and Kozak, {Kevin R.} and Remmel, {Rory P.} and Marnett, {Lawrence J.}",
year = "2000",
month = "1",
day = "18",
doi = "10.1073/pnas.97.2.925",
language = "English (US)",
volume = "97",
pages = "925--930",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "2",

}

TY - JOUR

T1 - Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors

T2 - Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors

AU - Kalgutkar, Amit S.

AU - Crews, Brenda C.

AU - Rowlinson, Scott W.

AU - Marnett, Alan B.

AU - Kozak, Kevin R.

AU - Remmel, Rory P.

AU - Marnett, Lawrence J.

PY - 2000/1/18

Y1 - 2000/1/18

N2 - All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.

AB - All nonsteroidal antiinflammatory drugs (NSAIDs) inhibit the cyclooxygenase (COX) isozymes to different extents, which accounts for their anti-inflammatory and analgesic activities and their gastrointestinal side effects. We have exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selective COX-2 inhibitors. Derivatization of the carboxylate moiety in moderately selective COX-1 inhibitors, such as 5,8,11,14-eicosatetraynoic acid (ETYA) and arylacetic and fenamic acid NSAIDs, exemplified by indomethacin and meclofenamic acid, respectively, generated potent and selective COX-2 inhibitors. In the indomethacin series, esters and primary and secondary amides are superior to tertiary amides as selective inhibitors. Only the amide derivatives of ETYA and meclofenamic acid inhibit COX-2; the esters are either inactive or nonselective. Inhibition kinetics reveal that indomethacin amides behave as slow, tight-binding inhibitors of COX-2 and that selectivity is a function of the time-dependent step. Site-directed mutagenesis of murine COX-2 indicates that the molecular basis for selectivity differs from the parent NSAIDs and from diarylheterocycles. Selectivity arises from novel interactions at the opening and at the apex of the substrate-binding site. Lead compounds in the present study are potent inhibitors of COX-2 activity in cultured inflammatory cells. Furthermore, indomethacin amides are orally active, nonulcerogenic, anti-inflammatory agents in an in vivo model of acute inflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.

UR - http://www.scopus.com/inward/record.url?scp=0034681109&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0034681109&partnerID=8YFLogxK

U2 - 10.1073/pnas.97.2.925

DO - 10.1073/pnas.97.2.925

M3 - Article

C2 - 10639181

AN - SCOPUS:0034681109

VL - 97

SP - 925

EP - 930

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 2

ER -