Heterocyclic Building Blocks-Benzothiophene

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

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

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

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

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

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

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

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

Koen, Yakov M. published the artcileIdentification of Protein Targets of Reactive Metabolites of Tienilic Acid in Human Hepatocytes, Related Products of benzothiophene, the main research area is tienilic acid reactive metabolite hepatotoxicity protein target.

Tienilic acid (TA) is a uricosuric diuretic that was withdrawn from the market only months after its introduction because of reports of serious incidents of drug-induced liver injury including some fatalities. Its hepatotoxicity is considered to be primarily immunoallergic in nature. Like other thiophene compounds, TA undergoes biotransformation to a S-oxide metabolite which then reacts covalently with cellular proteins. To identify protein targets of TA metabolites, we incubated [14C]-TA with human hepatocytes, separated cellular proteins by 2D gel electrophoresis, and analyzed proteins in 36 radioactive spots by tryptic digestion followed by LC-MS/MS. Thirty-one spots contained at least one identifiable protein. Sixteen spots contained only one of 14 nonredundant proteins which were thus considered to be targets of TA metabolites. Six of the 14 were also found in other radioactive spots that contained from 1 to 3 addnl. proteins. Eight of the 14 had not been reported to be targets for any reactive metabolite other than TA. The other 15 spots each contained from 2 to 4 identifiable proteins, many of which are known targets of other chem. reactive metabolites, but since adducted peptides were not observed, the identity of the adducted protein(s) in these spots is ambiguous. Interestingly, all the radioactive spots corresponded to proteins of low abundance, while many highly abundant proteins in the mixture showed no radioactivity. Furthermore, of approx. 16 previously reported protein targets of TA in rat liver, only one (fumarylacetoacetase) is among the 14 targets identified in this work. One reason for this difference may be statistical, given that each study identified a small number of targets from among thousands present in hepatocytes. Another may be the species difference (i.e., rat vs human), and still another may be the method of detection of adducted proteins (i.e., Western blot vs C-14). Knowledge of human target proteins is very limited. Of more than 350 known protein targets of reactive metabolites, only 42 are known from humans, and only 21 of these are known to be targets for more than one chem. Nevertheless, the demonstration that human target proteins can be identified using isolated hepatocytes in vitro should enable the question of species differences to be addressed more fully in the future.

Chemical Research in Toxicology 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, Related Products of benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Zhu, Xiao published the artcileConstruction and analysis of a human hepatotoxicity database suitable for QSAR modeling using post-market safety data, Formula: C13H8Cl2O4S, the main research area is human hepatotoxicity database liver injury; Drug-induced liver injury; Post-market safety; Predictive toxicology; QSAR.

Drug-induced liver injury (DILI) is one of the most common drug-induced adverse events (AEs) leading to life-threatening conditions such as acute liver failure. It has also been recognized as the single most common cause of safety-related post-market withdrawals or warnings. Efforts to develop new predictive methods to assess the likelihood of a drug being a hepatotoxicant have been challenging due to the complexity and idiosyncrasy of clin. manifestations of DILI. The FDA adverse event reporting system (AERS) contains post-market data that depict the morbidity of AEs. Here, we developed a scalable approach to construct a hepatotoxicity database using post-market data for the purpose of quant. structure-activity relation (QSAR) modeling. A set of 2029 unique and modelable drug entities with 13,555 drug-AE combinations was extracted from the AERS database using 37 hepatotoxicity-related query preferred terms (PTs). To determine the optimal classification scheme to partition pos. from neg. drugs, a manually-curated DILI calibration set composed of 105 negatives and 177 positives was developed based on the published literature. The final classification scheme combines hepatotoxicity-related PT data with supporting information that optimize the predictive performance across the calibration set. Data for other toxicol. endpoints related to liver injury such as liver enzyme abnormalities, cholestasis, and bile duct disorders, were also extracted and classified. Collectively, these datasets can be used to generate a battery of QSAR models that assess a drug’s potential to cause DILI.

Toxicology published new progress about Databases. 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