2000
DOI: 10.1021/jm000004e
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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… Show more

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Cited by 302 publications
(253 citation statements)
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“…Since PGE 2 is formed by cyclooxygenase 1 and 2 (COX1 and COX2) from arachidonic acid, cells were pretreated with the COX inhibitors acetylsalicylic acid (ASA, 2 mM) [40] and indomethacin (Indo, 50 μM) [41]. The results showed a decrease of 80% in the PGE 2 release, as expected, from blocking the endogenous activity of COX (Fig.…”
Section: Rapid Uva-induced Synthesis Of Prostaglandin E 2 In Slo-hk Isupporting
confidence: 57%
“…Since PGE 2 is formed by cyclooxygenase 1 and 2 (COX1 and COX2) from arachidonic acid, cells were pretreated with the COX inhibitors acetylsalicylic acid (ASA, 2 mM) [40] and indomethacin (Indo, 50 μM) [41]. The results showed a decrease of 80% in the PGE 2 release, as expected, from blocking the endogenous activity of COX (Fig.…”
Section: Rapid Uva-induced Synthesis Of Prostaglandin E 2 In Slo-hk Isupporting
confidence: 57%
“…Interestingly, the 2′-methyl group of indomethacin is critical for inhibitory potency in the neutral amide and ester series, as the des-methyl derivatives are extremely poor inhibitors of the COX enzymes. 73,86 Structureactivity studies with diclofenac analogues indicate that methyl or chlorine substituents on the lower aniline ring in the ortho position are necessary to achieve potent inhibition of COX. 88 An o,o-difluoro substituted analogue is considerably less active, and compounds that are synthesized to resemble hydroxylated metabolites of diclofenac show inhibitory potencies that are 100 times lower than that of diclofenac.…”
Section: Cyclooxygenase Enzymes: Structure and Mechanismsmentioning
confidence: 99%
“…Cyclooxygenase enzyme exists in two distinct isoforms, a constitutive form (COX-1) and an inducible form (COX-2); the constitutive COX-1 is responsible for the maintenance of physiological functions, such as protection of gastric mucosa, vascular homeostasis and platelet aggregation [4][5][6] . Unlike COX-1, the COX-2 isoform is induced in response to mitogenic and pro-inflammatory stimuli and it is responsible for the progression of inflammation 7,8 .…”
Section: Introductionmentioning
confidence: 99%
“…Unlike COX-1, the COX-2 isoform is induced in response to mitogenic and pro-inflammatory stimuli and it is responsible for the progression of inflammation 7,8 . Thus, selective COX-2 inhibitor drugs (coxibs) as celecoxib (1), rofecoxib (2) and valdecoxib (3) were more useful for the treatment of inflammation and inflammation-associated disorders than the non-selective traditional NSAIDs as aspirin (4), ibuprofen (5) and indomethacin (6) (Figure 1). Unfortunately, some cardiovascular side effects including the increased incidences of high blood pressure and myocardial infarction accompanied the highly selective COX-2 inhibitors were attributed to the biochemical changes in the COX pathway 9,10 .…”
Section: Introductionmentioning
confidence: 99%