Category: 40180-04-9

Chen, Minjun published the artcileA Model to predict severity of drug-induced liver injury in humans, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is human drug liver injury.

Drug-induced liver injury (DILI) is a major public health concern, and improving its prediction remains an unmet challenge. Recently, we reported the Rule-of-2 (RO2) and found lipophilicity (logP ≥3) and daily dose ≥100 mg of oral medications to be associated with significant risk for DILI; however, the RO2 failed to estimate grades of DILI severity. In an effort to develop a quant. metrics, we analyzed the association of daily dose, logP, and formation of reactive metabolites (RM) in a large set of Food and Drug Administration-approved oral medications and found factoring RM into the RO2 to highly improve DILI prediction. Based on these parameters and by considering n = 354 drugs, an algorithm to assign a DILI score was developed. In univariate and multivariate logistic regression analyses the algorithm (i.e., DILI score model) defined the relative contribution of daily dose, logP, and RM and permitted a quant. assessment of risk of clin. DILI. Furthermore, a clear relationship between calculated DILI scores and DILI risk was obtained when applied to three independent studies. The DILI score model was also functional with drug pairs defined by similar chem. structure and mode of action but divergent toxicities. Specifically, for drug pairs where the RO2 failed, the DILI score correctly identified toxic drugs. Finally, the model was applied to n = 159 clin. cases collected from the National Institutes of Health’s LiverTox database to demonstrate that the DILI score correlated with the severity of clin. outcome. Conclusions: Based on daily dose, lipophilicity, and RM, a DILI score algorithm was developed that provides a scale of assessing the severity of DILI risk in humans associated with oral medications. (Hepatol. 2016;64:931-940).

Hepatology (Hoboken, NJ, United States) published new progress about Drug toxicity. 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

Darnell, Malin published the artcileSignificantly Different Covalent Binding of Oxidative Metabolites, Acyl Glucuronides, and S-Acyl CoA Conjugates Formed from Xenobiotic Carboxylic Acids in Human Liver Microsomes, Related Products of benzothiophene, the main research area is metabolite acyl glucuronide xenobiotic human liver microsome.

Xenobiotic carboxylic acids may be metabolized to oxidative metabolites, acyl glucuronides, and/or S-acyl-CoA thioesters (CoA conjugates) in vitro, e.g., in hepatocytes, and in vivo. These metabolites can potentially be reactive species and bind covalently to tissue proteins and are generally considered to mediate adverse drug reactions in humans. Acyl glucuronide metabolites have been the focus of reactive metabolite research for decades, whereas drug-CoA conjugates, which have been shown to be up to 40-70 times more reactive, have been given much less attention. In an attempt to dissect the contribution of different pathways to covalent binding, we utilized human liver microsomes supplemented with NADPH, uridine 5′-diphosphoglucuronic acid (UDPGA), or CoA to evaluate the reactivity of each metabolite sep. Seven carboxylic acid drugs were included in this study. While ibuprofen and tolmetin are still on the market, ibufenac, fenclozic acid, tienilic acid, suprofen, and zomepirac were stopped before their launch or withdrawn. The reactivities of the CoA conjugates of ibuprofen, ibufenac, fenclozic acid, and tolmetin were higher compared to those of their corresponding oxidative metabolites and acyl glucuronides, as measured by the level of covalent binding to human liver microsomal proteins. The highest covalent binding was observed for ibuprofenyl-CoA and ibufenacyl-CoA, to levels of 1000 and 8600 pmol drug eq/mg protein, resp. In contrast and in agreement with the proposed P 450-mediated toxicity for these drug mols., the reactivities of oxidative metabolites of suprofen and tienilic acid were higher compared to the reactivities of their conjugated metabolites, with NADPH-dependent covalent binding of 250 pmol drug eq/mg protein for both drugs. The seven drugs all formed UDPGA-dependent acyl glucuronides, but none of these resulted in covalent binding. This study shows that, unlike studies with hepatocytes or in vivo, human liver microsomes provide an opportunity to investigate the reactivity of individual metabolites.

Chemical Research in Toxicology published new progress about Drug toxicity. 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

Beaune, Philippe H. published the artcileImmunotoxicology of the liver: adverse reactions to drugs, Category: benzothiophene, the main research area is liver immunotoxicol drug adverse reaction review.

A review, with 45 references Liver is a frequent target for drug-induced hepatitis. They can be classified in two categories: the hepatitis in which the drug or a metabolite reach a vital target in the cell and the hepatitis in which the drug triggers an adverse immune response directed against the liver. We will discuss essentially this second kind of disease. They have key clin. features such as the low frequency, the dose independence, the delay between the beginning of drug intake and the triggering of the disease, the shortening of the delay upon rechallenge and very often the presence of autoantibodies in the serum of the patients. Such signs were found in hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine, anticonvulsants. They will be taken as examples to show the recent progress in the understanding of the mechanisms leading to the disease. It has been postulated that the drug is metabolized into a reactive metabolite binding to the enzyme which generated it; therefore the neoantigen might trigger an immune response characterized by the production of antibodies recognizing the native and or the modified protein. Most of these steps were proven in the cases of halothane, tienilic acid and dihydralazine. Several points seem important in the development of the disease: the equilibrium between toxication and detoxication pathways, the nature and amount of neoantigen, the individual immune response. However, many points remain unclear: for instance, the reason for the very low frequency of this kind of disease; the precise mechanism of the adverse immune response; the risk factors for developing such adverse reactions. Efforts should be made to better understand the mechanisms of this kind of disease: for instance, an animal model, tests to identify drugs at risk for such reactions, the role of these drugs in the processing of P450s and the processing of the neoantigens for their presentation to the immune system.

Journal of Hepatology published new progress about Drug toxicity. 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

Mansuy, Daniel published the artcileMolecular structure and hepatotoxicity: compared data about two closely related thiophene compounds, Related Products of benzothiophene, the main research area is review thiophene compound hepatotoxicity metabolism structure; cytochrome P450 thiophene metabolism hepatotoxicity review; tienilic acid isomer hepatotoxicity structure review.

A review with 11 references Two closely related compounds, a diuretic drug tienilic acid (TA) and its isomer TAI have been found to exert very different toxic effects. In human liver microsomes TA is oxidized mainly by CYP 2C9 with formation of a reactive metabolite which covalently binds to CYP 2C9 in a rather specific manner. On the contrary, CYP 2C9-dependent oxidation of TAI leads to reactive metabolite(s) causing an intense covalent binding to several microsomal proteins. Based on these very different behaviors and fates of TA and TAI metabolites, it is proposed that the direct hepatotoxic effects of TAI could be due to an intense, non-specific covalent binding of its reactive metabolite(s) to liver proteins, whereas the toxic effects of the immunoallergic type of TA could be due to the very specific covalent binding of its sulfoxide metabolite to CYP 2C9.

Journal of Hepatology published new progress about Drug toxicity. 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

Odlind, Bo published the artcileTubular secretion and effects of tienilic acid in the hen, Product Details of C13H8Cl2O4S, the main research area is tienilic acid kidney tubule secretion.

The relationship between renal tubular secretion of the uricosuric diuretic tienilic acid (I) [40180-04-9] (10 or 30 μg/kg/min) and its saluretic effects was determined in hens using a modified Sperber technique. A true tubular excretion fraction (TTEF) of 29.9% (mean) for tienilic acid was reduced by novobiocin to 3.3%. This demonstrates active tubular secretion of the diuretic by an organic anion transport system in the hen kidney. Infusion of the diuretic into one leg vein caused a marked ipsilateral excess excretion of Cl-, Na+, and K+; these effects were reduced by novobiocin. Thus, in the hen a significant part of the saluretic effect of tienilic acid depends on the active secretion of the drug by tubular cells, as has previously been found for 3 loop diuretics i.e. ethacrynic acid, furosemide and piretanide. Apparently, the saluretic effect of tienilic acid is evoked mainly from the luminal side of the avian nephron. At an infusion rate of 20 μg/kg/min of tienilic acid, a marked saluresis occurred; there was, however, no effect on the urinary urate excretion.

European Journal of Pharmacology published new progress about Kidney tubule. 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, Product Details of C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Lechi, A. published the artcileAn evaluation of tienilic acid, a new diuretic uricosuric agent, in the therapy of arterial hypertension, Product Details of C13H8Cl2O4S, the main research area is tienilate hydrochlorothiazide hypertension.

Tienilic acid (I) [40180-04-9] and hydrochlorothiazide (II) [58-93-5] (250 and 50 mg/day, resp.) produced similar decreases in blood pressure and similar changes in plasma or serum electrolytes, urea, creatinine, glucose, cholesterol, and triglycerides and in creatinine clearance in hypertensive patients. I caused a significant decrease in serum uric acid [69-93-2] and an increase in urate clearance, whereas II produced a small increase in serum uric acid but had no effect on urate clearance. Thus, the diuretic and antihypertensive actions of I and II are very similar; the uricosuric/hypouricemic effect of I could assume clin. relevance in long-term therapy of hypertensive patients.

Clinical Science published new progress about Blood plasma. 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, Product Details of C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Sykes, Matthew J. published the artcilePrediction of Metabolism by Cytochrome P450 2C9: Alignment and Docking Studies of a Validated Database of Substrates, Related Products of benzothiophene, the main research area is cytochrome P450 2C9 substrate docking metabolism.

A validated database of 70 mols. known to undergo biotransformation by CYP2C9 was collated. The mol. alignment program ROCS was used with the query mol. flurbiprofen as a basis for predicting the correct active site orientation of the CYP2C9 database mols. The quality of the results obtained was excellent, with 39 of the first 44 mols. (89%) sorted by ROCS combination score having alignments that accounted for the exptl. observed site of oxidation Transposition of the first 39 correctly aligned mols. into the CYP2C9 active site yielded an average site of metabolism to iron heme distance of 5.21 A, in good agreement with previous exptl. observations. Mol. docking studies were also undertaken, but the results were less successful than the ROCS-based alignment method, indicating that ligand-based approaches with chem. typing are important in the prediction of metabolism by CYP2C9.

Journal of Medicinal Chemistry published new progress about Conformation. 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

Lewis, David F. V. published the artcileOn the estimation of binding affinity (ΔGbind) for human P450 substrates (based on Km and KD values), Synthetic Route of 40180-04-9, the main research area is P450 binding energy method drug substrate QSAR.

A straightforward methodol., based on first principles, for the estimation of human cytochrome P 450-substrate binding energies is outlined, and the system has then been applied successfully to a relatively large dataset of P 450 substrates totaling 90 compounds The results of Quant. Structure-Activity Relationship (QSAR) anal. on the same dataset of cytochrome P 450 (CYP) substrates from the CYP1, CYP2, and CYP3 families, involving a total of 90 compounds, agree favorably with the original anal. based on first principles, thus confirming the use of average values for hydrogen bond and π-π stacking energies, together with utilizing log P values as an estimation of desolvation energies. This method is based on a linear summation of the various contributary factors to the process, including: desolvation, hydrogen bonding, π-π stacking, restricted bond rotation and other energies relating to loss in translational and rotational energy. It is found that, for the majority of P 450 substrates investigated, the first four terms are required for a relatively good estimation (R = 0.98) of the substrate binding affinity (ΔGbind) towards CYP1 and CYP2 enzymes. Consequently, it would appear that the loss in rotational and translational energy, which is thought to occur on substrate binding, apparently has little effect in most cases, possibly due to some degree of residual motion of the enzyme-substrate complex within the endoplasmic reticulum membrane. However, the appearance of a small constant term in the QSAR equation could possibly relate to an average loss in translational and rotational energy for the 90 compounds studied in this investigation.

Current Drug Metabolism published new progress about Binding energy. 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, Synthetic Route of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Stueber, Wolfgang published the artcileDetermination of ethacrynic and tienilic acid in plasma by gas-liquid chromatography-mass spectrometry, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is ethacrynate tienilate determination blood; gas chromatog ethacrynate tienilate; mass spectrometry ethacrynate tienilate.

ethacrynic acid (I) [58-54-8] and tienilic acid (II) [40180-04-9] were extracted from plasma with (Et)2O. I and II were derivatized with pentafluorobenzyl bromide before being subjected to gas chromatog. on a column packed with 1% OV-17 on Chromosorb W, 80-100 mesh, with He as the carrier gas and the column temperature increasing from 200 to 300° at 30°/min. Using mass spectrometry in the electron-impact mode, detection of the mol. ion peak was possible for both I and II (m/e = 511 and 483, resp.). The recoveries of I and II were 94.5 and 95%, resp. Linear regression of the calibration graph gave a value of 0.998 for 0.5-1μg/mL and the limit of detection was ∼10-20 ng/mL plasma.

Journal of Chromatography, Biomedical Applications published new progress about Blood 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, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Vukusic, Ivo published the artcileQuantitative thin-layer chromatographic determination of ticrynafen in canine plasma, SDS of cas: 40180-04-9, the main research area is ticrynafen determination blood; chromatog thin layer ticrynafen blood.

After extraction from plasma with CHCl3, ticrynafen (I) [40180-04-9] was chromatographed on silica-gel K6F thin-layer-chromatog. plates with EtOAc-HOAc (95:5) as the developing solvent. I was determined with a dual-wavelength thin-layer-chromatog. scanner, using 300 nm and 400 nm as the dual wavelengths. The lowest amount of I detectable was 0.1 μg/spot (33 μg/mL), and linear responses were obtained up to 7.5 μg/spot. The relative standard deviations for plasma samples of 3.3-25.0 μg/mL ranged 3.6-13.6%. Recoveries were 75.3% at 3.3 μg/mL and 82.3% at 16.7 μg/mL. The accuracy of the assay was good, the difference between the observed and theor. concentrations for plasma samples of 1.0-7.5 μg/spot being 5.2%. The assay was used to determine I pharmacokinetics in the dog.

Journal of Chromatography, Biomedical Applications published new progress about Blood 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, SDS of cas: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem