Chemical and Biological Studies on Indomethacin, Sulindac and their Analogs

Shen, T. Y.; Winter, Charles A.

doi:10.1016/b978-0-12-013312-3.50007-8

Cited by 160 publications

(77 citation statements)

References 272 publications

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“…Indomethacin is clinically used for its potent anti-inflammatory, antipyretic, and analgesic properties, although it also has unwanted side effects causing various complications such as gastrointestinal injury (21). Both of such pharmaceutical and unwanted side effects of indomethacin are primarily ascribed to its potent inhibitory activity against COXs (22).…”

Section: Discussionmentioning

confidence: 99%

“…It was reported that IC 50 values for indomethacin on COX-1 and COX-2 in intact cells were 0.01 M and 0.6 M, respectively (16), and that the peak plasma level of indomethacin after the usual therapeutic dose of 25 mg in humans was 0.8 g/ml (2.2 M) (21). In this study, we demonstrated that indomethacin can fully activate CRTH2 at submicromolar concentrations in Th2 cells, basophils, and eosinophils.…”

Section: Discussionmentioning

confidence: 99%

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Cutting Edge: Agonistic Effect of Indomethacin on a Prostaglandin D2 Receptor, CRTH2

Hirai

Tanaka²,

Takano³

et al. 2002

The Journal of Immunology

135

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Indomethacin is a widely used nonsteroidal anti-inflammatory drug and is generally known to exhibit its multiple biological functions by inhibiting cyclooxygenases or activating peroxisome proliferator-activated receptors. In this study, we present evidence demonstrating that the novel PGD2 receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) is another functional target for indomethacin. Indomethacin induced Ca2+ mobilization in CRTH2-transfected K562 cells at submicromolar concentrations (approximate EC50, 50 nM) in a Gαi-dependent manner as PGD2 did. Other nonsteroidal anti-inflammatory drugs (aspirin, sulindac, diclofenac, and acemetacin) had no such effect even at micromolar concentrations. In chemotaxis assay, three CRTH2-expressing cell types, Th2 cells, eosinophils, and basophils, were all significantly attracted by indomethacin (EC50, 50–500 nM) as well as by PGD2 (EC50, 2–20 nM), and the effects of indomethacin were blocked by anti-CRTH2 mAb. These results suggest the involvement of CRTH2 in mediating some of therapeutic and/or unwanted side effects of indomethacin, independently of cyclooxygenases and peroxisome proliferator-activated receptors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cutting Edge: Agonistic Effect of Indomethacin on a Prostaglandin D2 Receptor, CRTH2

Hirai

Tanaka²,

Takano³

et al. 2002

The Journal of Immunology

135

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“…In order to characterize the factor released from the endothelium by NA, experiments were repeated with proximal LCA segments in the presence of either indomethacin, 10-5M, or methylene blue, 3 x 106 M, which inhibits formation of cyclo-oxygenase products (Shen & Winter, 1977) and of guanosine 3':5'-cyclic monophosphate (cyclic GMP) by soluble guanyl-cyclase, respectively (Holzmann, 1982;Martin et al, 1985).…”

Section: Methodsmentioning

confidence: 99%

Action of noradrenaline on isolated proximal and distal coronary arteries of rat: selective release of endothelium‐derived relaxing factor in proximal arteries

Nyborg

1990

British J Pharmacology

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1 The effect of noradrenaline (NA) on the vascular smooth muscle and endothelial cells in isolated ring segments from the proximal and distal part of the left coronary artery (LCA) in rats was examined. 2 NA had a weak concentration-dependent contractile effect on proximal but relaxed distal segments of the LCA. The maximal NA-induced contraction of the proximal segments was doubled while the relaxation of the distal LCA segments was converted to a contraction after blockade of fB-adrenoceptors with propranolol 3 x 10-6 M, thus indicating the presence of both a-and fi-adrenoceptors in the arteries, with dominance of a-adrenoceptors and of f-adrenoceptors in the proximal and distal segments of the LCA, respectively.3 The contractile effect of NA (8-adrenoceptors blocked) was doubled in the proximal LCA segments after the endothelium was removed. Endothelial denudation had, in contrast, no potentiating effect on the contractile response of the distal arteries to NA. Both proximal and distal segments became more sensitive to the contractile action of NA after removal of the endothelium. 4 The spontaneous myogenic tone increased in both proximal and distal LCAs after endothelial removal, indicating spontaneous release of a relaxing endothelial factor in the vessels.5 Following contraction with prostaglandin F2. (PGF2j), and in the presence of propranolol, 3 x 10-6 M, and prazosin, 10-6 M, NA induced an endothelium-dependent relaxation of only proximal but not distal segments of the precontracted LCA. The NA-induced relaxation of the proximal segments of the LCA was not altered by indomethacin 10-M but was completely abolished after incubation with methylene blue, 3 x 10-6 M, or following endothelium removal. These results are compatible with NA-induced release of EDRF in these arteries. 6 The selective a2-adrenoceptor agonist, B-HT 933, only induced a weak relaxation of PGF2,-precontracted proximal (endothelium intact) LCA segments at a concentration of 10-4M. The NA-induced relaxation of these vessels was unaffected by incubating the vessels with 10-IM B-HT 933.The NA relaxation response curve was shifted ca 1.1 log unit to the right by rauwolscine, 1o-6M, giving an estimated pA2-value of 7.12. The receptor through which NA activates the endothelium appears to be of an atypical a2-subtype.

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“…Compound 2 was synthesized by a route that mimicked the synthesis of sulindac sulfide (Supplementary Scheme 1) (18). p-Fluorophenylpropionic acid was cyclized to the indanone then alkylated via a Reformatsky reaction.…”

mentioning

confidence: 99%

Desmethyl Derivatives of Indomethacin and Sulindac as Probes for Cyclooxygenase-Dependent Biology

Felts¹,

Ji²,

Stafford³

et al. 2007

ACS Chem. Biol.

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Cyclooxygenases (COX) have been implicated in the etiology of a number of diseases, but defining the precise contribution of COXs to these diseases is challenging. Potent COX inhibitors exist, but they display off-target effects. 2′-Desmethyl derivatives of indomethacin and sulindac sulfide were synthesized that demonstrated reduced COX inhibitory activity but were inducers of peroxisome proliferator-activated receptor γ-dependent transcription, adipocyte differentiation, or apoptosis of colon cancer cell lines. 2′-Desmethylindomethacin demonstrated gastrointestinal toxicity lower than that of indomethacin in C57BL6 mice, highlighting the importance of COX activity in maintaining gastrointestinal homeostasis and establishing that COX inhibition contributes to gastrointestinal toxicity by nonsteroidal antiinflammatory drugs. These compounds serve as useful probes of COX-dependent biology and may represent leads for antidiabetic and anticancer drugs.

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Chemical and Biological Studies on Indomethacin, Sulindac and their Analogs

Cited by 160 publications

References 272 publications

Cutting Edge: Agonistic Effect of Indomethacin on a Prostaglandin D2 Receptor, CRTH2

Cutting Edge: Agonistic Effect of Indomethacin on a Prostaglandin D2 Receptor, CRTH2

Action of noradrenaline on isolated proximal and distal coronary arteries of rat: selective release of endothelium‐derived relaxing factor in proximal arteries

Desmethyl Derivatives of Indomethacin and Sulindac as Probes for Cyclooxygenase-Dependent Biology

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