Synthesis and Biological Evaluation of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors:  Identification of 4-[5-(4-Methylphenyl)-3- (trifluoromethyl)-1<i>H</i>-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib)

Td, Penning; Jj, Talley; Bertenshaw,; Js, Carter; Collins, P.; Docter, Stephen H.; Mj, Graneto; Lf, Lee; Jw, Malecha; Jm, Miyashiro; Rs, Rogers; Dj, Rogier; Yu, Shiying; AndersonGD,; Eg, Burton; Jn, Cogburn; Sa, Gregory; Cm, Koboldt; We, Perkins; Seibert, Karen; Aw, Veenhuizen; Yy, Zhang; Pc, Isakson

doi:10.1021/jm960803q

Cited by 1,858 publications

(745 citation statements)

References 21 publications

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“…Since celecoxib specifically inhibits COX-2 (IC 50 = 0.04 µM for COX-2, compared with IC 50 = 15 µM for COX-1) [25], an increase in its plasma concentration in patients expressing CYP2C9*3 allelic variants might be expected. However, it seems possible that other CYP enzymes may partially compensate for reduced CYP2C9 activity.…”

Section: Discussionmentioning

confidence: 99%

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Sandberg

Yaşar

Strömberg

et al. 2002

Brit J Clinical Pharma

102

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Aims Celecoxib is a novel selective cyclooxygenase-2 inhibitor, which is subject to extensive hepatic metabolism. The aims of the present in vitro investigation were 1) to compare the rate of celecoxib hydroxylation by different genetic variants of cytochrome P450 2C9 (CYP2C9), and 2) to identify the enzyme(s) involved in the formation of the major metabolite carboxycelecoxib. Methods Hydroxycelecoxib formation was studied in human liver microsomes from 35 genotyped livers, as well as in yeast microsomes with recombinant expression of different P450 variants. Carboxycelecoxib formation was studied in liver microsomes incubated in the absence or presence of liver cytosol. The metabolites were identified and quantified by h.p.l.c. In addition, hydroxycelecoxib oxidation by different variants of recombinant human alcohol dehydrogenase (ADH1-3) was analysed by spectrophotometric monitoring of NADH generation from NAD + . Results The intrinsic clearance of celecoxib hydroxylation was significantly lower for yeast-expressed CYP2C9.3 (0.14 ml min − 1 nmol − 1 enzyme) compared with CYP2C9.1 (0.44 ml min − 1 nmol − 1 enzyme). In human liver microsomes, a significant 2-fold decrease in the rate of hydroxycelecoxib formation was evident in CYP2C9 * 1/ * 3 samples compared with CYP2C9 * 1/ * 1 samples. There was also a marked reduction (up to 5.3 times) of hydroxycelecoxib formation in a liver sample genotyped as CYP2C9 * 3/ * 3 . However, the CYP2C9 * 2 samples did not differ significantly from CYP2C9 * 1 in any of the systems studied. Inhibition experiments with sulphaphenazole (SPZ) or triacetyloleandomycin indicated that celecoxib hydroxylation in human liver microsomes was mainly dependent on CYP2C9 and not CYP3A4. The further oxidation of hydroxycelecoxib to carboxycelecoxib was completely dependent on liver cytosol and NAD + . Additional experiments showed that ADH1 and ADH2 catalysed this reaction in vitro with apparent K m values of 42 µ M and 10 µ M , respectively, whereas ADH3 showed no activity. Conclusions The results confirm that CYP2C9 is the major enzyme for celecoxib hydroxylation in vitro and further indicate that the CYP2C9 * 3 allelic variant is associated with markedly slower metabolism. Furthermore, it was shown for the first time that carboxycelecoxib formation is dependent on cytosolic alcohol dehydrogenase, presumably ADH1 and/or ADH2.

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Section: Discussionmentioning

confidence: 99%

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Sandberg

Yaşar

Strömberg

et al. 2002

Brit J Clinical Pharma

102

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“…Concentrationrelaxation curves to 0.1 nM-10 mM BK were performed in arteries previously contracted using 0.1 mM Phe. In some preparations, the endothelium was mechanically removed or the rings were incubated with 10 mM indomethacin for 45 min, 500 mM valeryl salicylate for 1 h (Bhattacharyya et al, 1995) or 0.1 mM celecoxib for 1 h (Penning et al, 1997).…”

Section: Vascular Studiesmentioning

confidence: 99%

The balloon catheter induces an increase in contralateral carotid artery reactivity to angiotensin II and phenylephrine

Accorsi‐Mendonça¹,

Corrêa²,

Paiva

et al. 2004

British J Pharmacology

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1 The effects of balloon injury on the reactivity of ipsilateral and contralateral carotid arteries were compared to those observed in arteries from intact animals (control arteries). 2 Carotid arteries were obtained from Wistar rats 2, 4, 7, 15, 30 or 45 days after injury and mounted in an isolated organ bath. Reactivity to angiotensin II (Ang II), phenylephrine (Phe) and bradykinin (BK) was studied. Curves were constructed in the absence or presence of endothelium or after incubation with 10 mM indomethacin, 500 mM valeryl salicylate or 0.1 mM celecoxib. 3 Phe, Ang II and BK maximum effects (Emax) were decreased in ipsilateral arteries when compared to control arteries. No differences were observed among pD2 or Hill coefficient. 4 Emax to Phe (4 and 7 days) and to Ang II (15 and 30 days) increased in the contralateral artery. In addition, Phe or Ang II reactivity was not significantly different in aorta rings from control or carotid-injured animals. 5 The increased responsiveness of contralateral artery was not due to changes in carotid blood flow or resting membrane potential. The endothelium-dependent inhibitory component is not present in the contraction of contralateral arteries and it is not related to superoxide anion production. 6 Indomethacin decreased contralateral artery responsiveness to Phe and Ang II. Valeryl salicylate reduced the Ang II response in contralateral and control arteries. Celecoxib decreased the Phe Emax of contralateral artery. 7 In conclusion, decreased endothelium-derived factors and increased prostanoids appear to be responsible for the increased reactivity of contralateral arteries after injury.

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“…The molecule SC-236 is a member of the family of the potent and selective inhibitors of COX-2 activity (23). Its selectivity toward COX-2 has been uniformly proven: it displays IC 50 values of 17 and 0.005 M against human COX-1 and COX-2, respectively.…”

Section: Figurementioning

confidence: 99%

Lipopolysaccharide-Induced Increase of Prostaglandin E2 Is Mediated by Inducible Nitric Oxide Synthase Activation of the Constitutive Cyclooxygenase and Induction of Membrane-Associated Prostaglandin E Synthase

Devaux¹,

Seguin²,

Grosjean

et al. 2001

The Journal of Immunology

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NO produced by the inducible NO synthase (NOS2) and prostanoids generated by the cyclooxygenase (COX) isoforms and terminal prostanoid synthases are major components of the host innate immune and inflammatory response. Evidence exists that pharmacological manipulation of one pathway could result in cross-modulation of the other, but the sense, amplitude, and relevance of these interactions are controversial, especially in vivo. Administration of 6 mg/kg LPS to rats i.p. resulted 6 h later in induction of NOS2 and the membrane-associated PGE synthase (mPGES) expression, and decreased constitutive COX (COX-1) expression. Low level inducible COX (COX-2) mRNA with absent COX-2 protein expression was observed. The NOS2 inhibitor aminoguanidine (50 and 100 mg/kg i.p.) dose dependently decreased both NO and prostanoid production. The LPS-induced increase in PGE2 concentration was mediated by NOS2-derived NO-dependent activation of COX-1 pathway and by induction of mPGES. Despite absent COX-2 protein, SC-236, a putative COX-2-specific inhibitor, decreased mPGES RNA expression and PGE2 concentration. Ketoprofen, a nonspecific COX inhibitor, and SC-236 had no effect on the NOS2 pathway. Our results suggest that in a model of systemic inflammation characterized by the absence of COX-2 protein expression, NOS2-derived NO activates COX-1 pathway, and inhibitors of COX isoforms have no effect on NOS2 or NOS3 (endothelial NOS) pathways. These results could explain, at least in part, the deleterious effects of NOS2 inhibitors in some experimental and clinical settings, and could imply that there is a major conceptual limitation to the use of NOS2 inhibitors during systemic inflammation.

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Synthesis and Biological Evaluation of the 1,5-Diarylpyrazole Class of Cyclooxygenase-2 Inhibitors: Identification of 4-[5-(4-Methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, Celecoxib)

Cited by 1,858 publications

References 21 publications

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

The balloon catheter induces an increase in contralateral carotid artery reactivity to angiotensin II and phenylephrine

Lipopolysaccharide-Induced Increase of Prostaglandin E2 Is Mediated by Inducible Nitric Oxide Synthase Activation of the Constitutive Cyclooxygenase and Induction of Membrane-Associated Prostaglandin E Synthase

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