Category: 40180-04-9

Nishiya, Takayoshi published the artcileInvolvement of cytochrome P450-mediated metabolism in tienilic acid hepatotoxicity in rats, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is tienilic acid glutathione adduct hepatotoxicity CYP450.

Tienilic acid is reported to be converted into electrophilic metabolites by cytochrome P 450 (CYP) in vitro. In vivo, however, the metabolites have not been detected and their effect on liver function is unknown. We previously demonstrated that tienilic acid decreased the GSH level and upregulated genes responsive to oxidative/electrophilic stresses, such as heme oxygenase-1 (Ho-1), glutamate-cysteine ligase modifier subunit (Gclm) and NAD(P)H dehydrogenase quinone 1 (Nqo1), in rat liver, as well as inducing hepatotoxicity by co-treatment with the glutathione biosynthesis inhibitor -buthionine-(S,R)-sulfoximine (BSO). In this study, for the first time, we identified a glutathione-tienilic acid adduct, a stable conjugate of putative electrophilic metabolites with glutathione (GSH), in the bile of rats given a single oral dose of tienilic acid (300 mg/kg). Furthermore, a tienilic acid-induced decrease in the GSH level and upregulation of Ho-1, Gclm and Nqo1 were completely blocked by pretreatment with the CYP inhibitor 1-aminobenzotriazole (ABT, 66 mg/kg, i.p.). The increase in the serum ALT level and hepatocyte necrosis resulting from the combined dosing of BSO and tienilic acid was prevented by ABT, despite a low hepatic GSH level. These findings suggest that the electrophilic metabolites of tienilic acid produced by CYP induce electrophilic/oxidative stresses in the rat liver and this contributes to the hepatotoxicity of tienilic acid under impaired GSH biosynthesis.

Toxicology Letters published new progress about Diuretics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Nishiya, Takayoshi published the artcileTienilic Acid Enhances Hyperbilirubinemia in Eisai Hyperbilirubinuria Rats through Hepatic Multidrug Resistance-Associated Protein 3 and Heme Oxygenase-1 Induction, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is diuretic tienilic acid hyperbilirubinemia liver MRP3 heme oxygenase hepatotoxicity.

We demonstrated that tienilic acid, a diuretic drug withdrawn from the market because of hepatic failure, enhanced hyperbilirubinemia in Eisai hyperbilirubinuria rats (EHBR) with a defect of canalicular multidrug resistance-associated protein 2 (Mrp2). In contrast, no remarkable changes were noted in Sprague-Dawley (SD) rats, the parent strain for EHBR. To investigate a mechanism underlying this enhanced hyperbilirubinemia, we focused on comprehensive effects of tienilic acid on clinicopathol. aspects and expression of hepatic transporters. Other than eventual hyperbilirubinemia with slightly increased biliary bilirubin, a single oral treatment of EHBR with tienilic acid at 300 mg/kg caused no changes in serum alanine aminotransferase and alk. phosphatase, bile flow rate and biliary bile acid secretion, or hepatic morphol. In analyses of mRNA expression of the hepatic transporters, elevated Mrp3 expression in EHBR correlated with an increase in serum total bilirubin, suggesting increased bilirubin transport from the liver into the peripheral blood flow. Hepatic heme oxygenase-1 (Ho-1) mRNA, a stress-induced isoform of the rate-limiting enzyme in the catabolism of heme to bilirubin, was markedly upregulated in EHBR at the same dose at which increased serum bilirubin was seen. A time-course study revealed that marked induction of Ho-1 occurred earlier than that of Mrp3, followed by an increase in serum bilirubin. These results suggest that hepatic Mrp3 and Ho-1 may contribute to tienilic acid-enhanced hyperbilirubinemia in EHBR by inducing increased bilirubin transport from the liver into the blood stream, preceded by potentiation of bilirubin formation in the liver.

Toxicological Sciences published new progress about Diuretics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Tolman, Keith G. published the artcileToxicity of uricosuric diuretics in rat hepatocyte culture, Category: benzothiophene, the main research area is uricosuric toxicity liver hepatocyte structure.

Several aryloxyacetic acid diuretics have shown hepatotoxicity in humans, yet there continues to be interest in developing these compounds because of their uricosuric properties. The hepatocyte monolayer culture associated, as a model for studying the compounds in vitro. An attempt was made to define the structural components that are associated with hepatotoxicity. Ticrynafen, indacrinone, ethacrynic acid, and A-49816 were toxic in hepatocyte cultures. With the exception of indacrinone, the toxicity was paralleling the experience in humans. The toxic compounds share a ketodichlorophenoxyacetic acid chem. structure (I). A-56234, an investigational uricosuric, was also toxic in cultures but was not hepatotoxic in limited clin. experience in humans. It does not possess the I structure proper but may be metabolized to a closely related structure. Furosemide, which does not have the I structure, was not toxic in hepatocyte cultures and has not been hepatotoxic in humans. Thus, the structure common to the toxic compounds is I or a closely related compound The hepatocyte monolayer system is a good model for demonstrating toxicity and/or predicting toxicity of new compounds

Biochemical Pharmacology published new progress about Diuretics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Higaki, Junko published the artcileChemical structure and toxicity of diuretics in isolated hepatocytes, Formula: C13H8Cl2O4S, the main research area is diuretic structure hepatocyte toxicity; tienilic acid analog structure activity; indacrinone analog structure activity.

The effects of several diuretics, including tienillic acid (I) and indacrinone (II) on isolated rat hepatocytes were examined Addition of I and II at 1 mM to a suspension of freshly isolated cells caused dose-dependent loss of cell viability as judged by the LDH-latency test. A survey of 19 structurally related compounds [III, IV, and V (R = 2-thienylcarbonyl, EtCO, Me2NSO2, MeNHSO2, or H2NSO2, X and Y = H, Cl, or Me)] revealed that the extent of cell injury and chem. structure were correlated, and an intense adverse effect was attributed to the 2-thienylcarbonyl moiety. Several other factors influencing cell viability are also disclosed. I and II were toxic to the primary culture of hepatocytes at a lower dose than that to freshly isolated hepatocytes. Thus, an isolated hepatocyte system can be used to select compounds displaying low hepatotoxicity, e.g., when screening diuretics.

Pharmacology & Toxicology (Oxford, United Kingdom) published new progress about Diuretics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Takagi, Shiro published the artcileHepatotoxicity of DR-3438, tienilic acid, indacrinone and furosemide studied in vitro, Computed Properties of 40180-04-9, the main research area is liver toxicity diuretic DR 3438; tienilic acid liver toxicity; indocrinone liver toxicity; furosemide liver toxicity.

A new diuretic antihypertensive, DR-3438 (I), and the 3 other title diuretic drugs were evaluated for their toxicity in vitro. Hepatocytes were isolated from male rats and incubated in medium containing various concentrations of DR-3438, tienilic acid, indacrinone or furosemide. Tienilic acid decreased cell viability and glutathione content in the hepatocytes and increased lipid peroxidation in these cells. Indacrinone also decreased cell viability, but neither cell viability nor glutathione content was affected by furosemide or DR-3438.

Toxicology Letters published new progress about Diuretics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Computed Properties of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Ahokas, Jorma T. published the artcileInhibition of purified rat liver glutathione S-transferase isozymes by diuretic drugs, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is glutathione transferase inhibition diuretic.

Seven soluble rat liver glutathione S-transferase  [50812-37-8] isozymes were isolated, and the inhibition of these isozymes by selected diuretics was investigated, using 1-chloro-2,4-dinitrobenzene as substrate. All the isozymes were inhibited to some extent, but there was significant isozyme-dependent selectivity of inhibition. The greatest inhibitory effect (80%) was found when phenoxyacetic acid-type diuretics and indacrynic acid  [56049-88-8] were incubated with glutathione S-transferase isozymes 3-3, 3-4, and 4-4. The sulfamoylbenzoic acid diuretics furosemide  [54-31-9] and bumetanide  [28395-03-1] had a lesser effect on the isozymes studied. As glutathione S-transferases are thought to play an important protective role in the various tissues of animals and man, by catalyzing the glutathione conjugation of electrophilic drugs and drug metabolites, their inhibition may be toxicol. important.

Biochemical Pharmacology published new progress about Diuretics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Ehrhardt, J. D. published the artcileNegative-ion mass spectra of methylated diuretics, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is diuretic methylation mass spectra analysis.

The neg.-ion mass spectra of 19 methylated diuretics are presented and correlations between these spectra and the chem. structures of the compounds are indicated. The spectra are of interest as the basis of an anal. method for the identification of small quantities of diuretics in the urine of hypokalemic patients.

Rapid Communications in Mass Spectrometry published new progress about Diuretics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Koga, Hiroshi published the artcileStudies on uricosuric diuretics. 4. Three-dimensional structure-activity relationships and receptor mapping of (aryloxy)acetic acid diuretics, Formula: C13H8Cl2O4S, the main research area is aryloxyacetate diuretic structure activity receptor model.

A receptor model was created for (aryloxy)acetic acid diuretics based on the enhanced diuretic activity of indacrinone (I) and a tienilic acid analog (II) when compared with tienilic acid (III). The degree of fitting to this receptor model was related to the diuretic activity of a series of (aryloxy)acetic acid analogs. Studies with addnl. analogs led to a modification of the receptor model which should be useful for future drug design.

Journal of Medicinal Chemistry published new progress about Diuretics. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Valadon, Philippe published the artcileThiophene Sulfoxides as Reactive Metabolites: Formation upon Microsomal Oxidation of a 3-Aroylthiophene and Fate in the Presence of Nucleophiles in Vitro and in Vivo, Related Products of benzothiophene, the main research area is microsome oxidation tienilic acid.

Oxidative metabolism of the 3-aroylthiophene tienilic acid (I) by rat liver microsomes in the presence of mercaptoethanol as a trapping agent led to the isolation of four main compounds, which have been isolated and characterized by UV, 1H NMR, and mass spectroscopy. They all derive from two primary metabolites (II diastereoisomers), which result from the nucleophilic addition of mercaptoethanol to a reactive, very electrophilic intermediate formed by sulfoxidation of the thiophene ring of I. Further reactions of II diastereoisomers with mercaptoethanol led a compound that is opened at the level of its thiophene ring and, eventually, to a final metabolite III, resulting formally from the addition of mercaptoethanol on the 4,5-double bond of the thiophene ring of I. III is very stable even in the presence of a large excess of mercaptoethanol. Similar reactions were observed upon microsomal oxidation of I in the presence of another thiol, N-acetylcysteine. Final metabolites (IV diastereoisomers), equivalent to III, except for the replacement of its mercaptoethanol substituent with an N-acetylcysteinyl group, were isolated and characterized by UV, 1H NMR, and mass spectroscopy. After treatment of rats with I, IV could be detected in urine, indicating that the successive reactions, that were observed in vitro after microsomal oxidation of I in the presence of a thiol-containing trapping agent, also occur in vivo, glutathione acting as a nucleophile in that case. These data provide evidence for the intermediate formation of a reactive, electrophilic thiophene sulfoxide in metabolic oxidation of I in vitro and in vivo. They also provide the first data on the complex reactivity of such thiophene sulfoxides, whose chem. is poorly known, and on their fates in living organisms.

Chemical Research in Toxicology published new progress about Microsome. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Related Products of benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Fujimoto, Kazunori published the artcileIn vitro cytotoxicity assay to evaluate the toxicity of an electrophilic reactive metabolite using glutathione-depleted rat primary cultured hepatocytes, Quality Control of 40180-04-9, the main research area is cytotoxicity assay glutathione depleted hepatocyte.

Glutathione plays an important role as not only a scavenger of reactive oxygen species but also in the conjugation or detoxification of electrophilic reactive metabolites, which has been thought to be one of the causes for idiosyncratic drug toxicity (IDT). Therefore, toxic responses to the reactive metabolites have been expected to be expressed more strongly in a glutathione-depleted condition. In the present study, we attempted to establish an in vitro cytotoxicity assay method to evaluate the toxicity of the reactive metabolite using rat primary cultured hepatocytes with cellular glutathione depletion by L-buthionine-S,R-sulfoximine. Also, we investigated whether the IDT risk is predictable by comparing the cytotoxic sensitivity between glutathione-depleted hepatocytes and untreated hepatocytes. Consequently, 10 drugs of 42 approved drugs, which were classified into 4 IDT categories (Withdrawn, Black box warning, Warning, and Safe), demonstrated higher cytotoxic sensitivity in the glutathione-depleted hepatocytes. Furthermore, a correlation was observed between the incidence of drugs with higher cytotoxic sensitivity in the glutathione-depleted hepatocytes and the IDT risk. The incidence was 50% in the Withdrawn category, 38% in the Black box warning category, 22% in the Warning category, and 8% in the Safe category. These results suggest that the IDT risk of some drugs may be predicted by comparing the cytotoxic sensitivity between them. Addnl., this method may be useful as a screening in the early stage of drug development where leads/candidates are optimized.

Chemico-Biological Interactions published new progress about Analysis. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Quality Control of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem