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Titolo:
Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors
Autore:
Kalgutkar, AS; Crews, BC; Rowlinson, SW; Marnett, AB; Kozak, KR; Remmel, RP; Marnett, LJ;
Indirizzi:
Vanderbilt Univ, Dept Biochem, Sch Med, AB Hancock Jr Mem Lab Canc Res,CtrMol Toxicol, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 l Toxicol, Nashville, TN 37232 USA Vanderbilt Univ, Dept Chem, Sch Med, Ctr Mol Toxicol, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 l Toxicol, Nashville, TN 37232 USA Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 Canc Ctr, Nashville, TN 37232 USA
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 2, volume: 97, anno: 2000,
pagine: 925 - 930
SICI:
0027-8424(20000118)97:2<925:BBDOC(>2.0.ZU;2-2
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROSTAGLANDIN G/H SYNTHASE-1; TIME-DEPENDENT INHIBITION; ENDOPEROXIDE SYNTHASE; ACTIVE-SITE; ACID; BINDING; ASPIRIN; AGENTS; BIOSYNTHESIS; ARGININE-120;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
43
Recensione:
Indirizzi per estratti:
Indirizzo: Marnett, LJ Vanderbilt Univ, Dept Biochem, Sch Med, AB Hancock Jr Mem Lab Canc Res,CtrMol Toxicol, 221 Kirkland Hall, Nashville, TN 37232 USA Vanderbilt Univ 221 Kirkland Hall Nashville TN USA 37232 2 USA
Citazione:
A.S. Kalgutkar et al., "Biochemically based design of cyclooxygenase-2 (COX-2) inhibitors: Facile conversion of nonsteroidal antiinflammatory drugs to potent and highly selective COX-2 inhibitors", P NAS US, 97(2), 2000, pp. 925-930

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. Wehave exploited biochemical differences between the two COX enzymes to identify a strategy for converting carboxylate-containing NSAIDs into selectiveCOX-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 afunction 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. Leadcompounds 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 acuteinflammation. Expansion of this approach can be envisioned for the modification of all carboxylic acid-containing NSAIDs into selective COX-2 inhibitors.

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Documento generato il 11/07/20 alle ore 10:11:18