Identification of urine metabolites of TFAP, a cyclooxygenase-1 inhibitor

Kakuta, Hiroki; Fukai, Ryosuke; Zheng, Xueli; Ohsawa, Fuminori; Bamba, Takeshi; Hirata, Kazumasa; Tai, Akihiro

doi:10.1016/j.bmcl.2010.01.161

Cited by 8 publications

(7 citation statements)

References 16 publications

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“…The development of COXIBs solved in part the selectivity problem in favor of COX-2 [4–5]. This effort was undertaken to reduce the gastrointestinal (GI) adverse effects associated with the poor COXs selectivity of most traditional NSAIDs, which was mistakenly associated with selective COX-1 inhibition [11–13]. Our discovery of 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) [7] (Fig.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Cingolani

Panella

Perrone

et al. 2017

European Journal of Medicinal Chemistry

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The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs.

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Section: Introductionmentioning

confidence: 99%

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Cingolani

Panella

Perrone

et al. 2017

European Journal of Medicinal Chemistry

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“…33−36 The other class of COX-1 inhibitors comprises substituted benzamides related to N -(5-amino-2-pyridinyl)-4-(trifluoromethyl)-benzamide (TFAP, 4 ; Figure 1). 25,37 This compound exhibits high COX-1 selectivity but has not been used extensively as a probe. TFAP and its analogues have been suggested as candidates for analgesics that do not cause stomach erosions or ulcers.…”

Section: Introductionmentioning

confidence: 99%

Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2′-Des-methyl-sulindac Sulfide Scaffold

et al. 2012

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Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclooxygenases (COX-1 and COX-2) followed by metabolism of endoperoxide intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2′-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

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“…] is the aryl‐benzanilidic structure prototype, bearing two aryls in E ‐like geometry . Although TFAP has some promising properties as a potent analgesic agent without gastric damage, it caused a red coloration of urine after oral administration in mice . Ultraviolet‐Visible (UV–VIS) spectra and liquid chromatography tandem‐mass spectrometry (LC–MS/MS) analyses performed on mice urine samples and metabolite candidates, revealed that the diaminopyridine metabolite, derived from TFAP amide bond hydrolysis, was responsible for the purple color of urine samples.…”

Section: New Noteworthy Cox‐1 Selective Inhibitors (2010–2015)mentioning

confidence: 56%

“…17 Although TFAP has some promising properties as a potent analgesic agent without gastric damage, it caused a red coloration of urine after oral administration in mice. 18 Ultraviolet-Visible (UV-VIS) spectra and liquid chromatography tandem-mass spectrometry (LC-MS/MS) analyses performed on mice urine samples and metabolite candidates, revealed that the diaminopyridine metabolite, derived from TFAP amide bond hydrolysis, was responsible for the purple color of urine samples. The modification of the diaminopyridine skeleton of TFAP led to the preparation of the 5-amino-2-ethoxy-N-(substituted)benzamide (ABEX) series that do not present the problem of colored metabolite.…”

Section: Benzamidesmentioning

confidence: 99%

COX‐1 Inhibitors: Beyond Structure Toward Therapy

Vitale

Panella

Scilimati

et al. 2016

Medicinal Research Reviews

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Biosynthesis of prostaglandins from arachidonic acid (AA) is catalyzed by cyclooxygenase (COX), which exists as COX-1 and COX-2. AA is in turn released from the cell membrane upon neopathological stimuli. COX inhibitors interfere in this catalytic and disease onset process. The recent prominent discovery involvements of COX-1 are mainly in cancer and inflammation. Five classes of COX-1 inhibitors are known up to now and this classification is based on chemical features of both synthetic compounds and substances from natural sources. Physicochemical interactions identification between such molecules and COX-1 active site was achieved through X-ray, mutagenesis experiments, specific assays and docking investigations, as well as through a pharmacometric predictive model building. All these insights allowed the design of new highly selective COX-1 inhibitors to be tested into those disease models in which COX-1 is involved. Particularly, COX-1 is expressed at high levels in the early to advanced stages of human epithelial ovarian cancer, and it also seems to play a pivotal role in cancer progression. The refinement of COX-1 selective inhibitor structure has progressed to the stage that some of the inhibitors described in this review could be considered as promising active principle ingredients of drugs and hence part of specific therapeutic protocols. This review aims to outline achievements, in the last 5 years, dealing with the identification of highly selective synthetic and from plant extracts COX-1 inhibitors and their theranostic use in neuroinflammation and ovarian cancer. Their gastrotoxic effect is also discussed.

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Identification of urine metabolites of TFAP, a cyclooxygenase-1 inhibitor

Cited by 8 publications

References 16 publications

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Structural basis for selective inhibition of Cyclooxygenase-1 (COX-1) by diarylisoxazoles mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6)

Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2′-Des-methyl-sulindac Sulfide Scaffold

COX‐1 Inhibitors: Beyond Structure Toward Therapy

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