Category: 40180-04-9

Robin, Marie-Anne published the artcileAntigenic targets in tienilic acid hepatitis. Both cytochrome P450 2C11 and 2C11-tienilic acid adducts are transported to the plasma membrane of rat hepatocytes and recognized by human sera, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is neoantigen tienilate cytochrome P 450 hepatitis.

Patients with tienilic acid hepatitis exhibit autoantibodies that recognize unalkylated cytochrome P 450 2C9 in humans but recognize 2C11 in rats. The aim of this study was to determine whether the immune reaction is also directed against neoantigens. Rats were treated with tienilic acid and hepatocytes were isolated. Immunoprecipitation, immunoblotting, and flow cytometry experiments were performed with an anti-tienilic acid or an anti-cytochrome P 450 2C11 antibody. Cytochrome P 450 2C11 was the main microsomal or plasma membrane protein that was alkylated by tienilic acid. Inhibitors of vesicular transport decreased flow cytometric recognition of both unalkylated and tienilic acid-alkylated cytochrome P 450 2C11 on the plasma membrane of cultured hepatocytes. Tienilic acid hepatitis sera that were preadsorbed on microsomes from untreated rats (to remove autoantibodies), poorly recognized untreated hepatocytes in flow cytometry experiments, but better recognized tienilic acid-treated hepatocytes. This recognition was decreased by adsorption with tienilic acid or by pre-exposure to the anti-tienilic acid or the anti-cytochrome P 450 2C11 antibody. The authors conclude that cytochrome P 450 2C11 is alkylated by tienilic acid and follows a vesicular route to the plasma membrane. Tienilic acid hepatitis sera contain antibodies against this tienilic acid adduct, in addition to the previously described anti-cytochrome P 450 autoantibodies.

Journal of Clinical Investigation published new progress about Autoantibodies Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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

Gong, Eun Chae published the artcileEnzyme kinetics and molecular docking studies on cytochrome 2B6, 2C19, 2E1, and 3A4 activities by sauchinone, Application In Synthesis of 40180-04-9, the main research area is liver microsome sauchinone cytochrome mol docking enzyme kinetics; CYP450; Saururus chinensis; docking; herb-drug interaction; human liver microsome; metabolic inhibition; sauchinone.

Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb-drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clin. application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational mol. docking anal. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing inhibition constant (Ki) values of 14.3, 16.8, 41.7, and 6.84μM, resp. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Mol. docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone-drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities.

Molecules published new progress about Amino acids Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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, Application In Synthesis of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Nishiya, Takayoshi published the artcileThe crucial protective role of glutathione against tienilic acid hepatotoxicity in rats, Application In Synthesis of 40180-04-9, the main research area is glutathione tienilic acid hepatotoxicity.

To investigate the hepatotoxic potential of tienilic acid in vivo, the authors administered a single oral dose of tienilic acid to Sprague-Dawley rats and performed general clinicopathol. examinations and hepatic gene expression anal. using Affymetrix microarrays. No change in the serum transaminases was noted at up to 1000 mg/kg, although slight elevation of the serum bile acid and bilirubin, and very mild hepatotoxic changes in morphol. were observed In contrast to the marginal clinicopathol. changes, marked upregulation of the genes involved in glutathione biosynthesis [glutathione synthetase and glutamate-cysteine ligase (Gcl)], oxidative stress response [heme oxygenase-1 and NAD(P)H dehydrogenase quinone 1], and phase II drug metabolism (glutathione S-transferase and UDP glycosyltransferase 1A6) were noted after 3 or 6 h postdosing. The hepatic reduced glutathione level decreased at 3-6 h, and then increased at 24 or 48 h, indicating that the upregulation of NF-E2-related factor 2 (Nrf2)-regulated gene and the late increase in hepatic glutathione are protective responses against the oxidative and(or) electrophilic stresses caused by tienilic acid. In a subsequent experiment, tienilic acid in combination with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of Gcl, caused marked elevation of serum alanine aminotransferase (ALT) with extensive centrilobular hepatocyte necrosis, whereas BSO alone showed no hepatotoxicity. The elevation of ALT by this combination was observed at the same dose levels of tienilic acid as the upregulation of the Nrf2-regulated genes by tienilic acid alone. Apparently, the impairment of glutathione biosynthesis may play a critical role in the development of tienilic acid hepatotoxicity through extensive oxidative and(or) electrophilic stresses.

Toxicology and Applied Pharmacology published new progress about Bile acids Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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, Application In Synthesis of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

McDonald, Matthew G. published the artcileModulation of major human liver microsomal cytochromes P450 by component alkaloids of goldenseal: time-dependent inhibition and allosteric effects, Synthetic Route of 40180-04-9, the main research area is human liver microsomal cytochrome alkaloid goldenseal allosteric effect.

Botanical and other natural products (NPs) are often coconsumed with prescription medications, presenting a risk for cytochrome P 450 (P 450)-mediated NP-drug interactions. The NP goldenseal (Hydrastis canadensis) has exhibited antimicrobial activities in vitro attributed to isoquinoline alkaloids contained in the plant, primarily berberine, (-)-β hydrastine, and to a lesser extent, hydrastinine. These alkaloids contain methylenedioxyphenyl rings, structural alerts with potential to inactivate P450s through formation of metabolic intermediate complexes. Time-dependent inhibition experiments were conducted to evaluate their ability to inhibit major P 450 activities in human liver microsomes by using a cocktail of isoenzyme-specific substrate probes. Berberine inhibited CYP2D6 (dextromethorphan O-demethylation; KI = 2.7μM, kinact = 0.065 min-1) and CYP3A4/5 (midazolam 1′-hydroxylation; KI = 14.8μM, kinact = 0.019 min-1); (-)-β-hydrastine inhibited CYP2C9 (diclofenac 4′-hydroxylation; KI = 49 ηM, kinact = 0.036 min-1), CYP2D6 (KI > 250μM, kinact > 0.06 min-1), and CYP3A4/5 (KI = 28μM, kinact = 0.056 min-1); and hydrastinine inhibited CYP2D6 (KI = 37μM, kinact = 0.049 min-1) activity. Berberine addnl. exhibited allosteric effects on midazolam hydroxylation, showing both pos. and neg. heterotropic cooperativity. Experiments with recombinant isoenzymes showed that berberine activated midazolam 1′-hydroxylation by CYP3A5, lowering Km(app), but showed mixed inhibition and neg. cooperativity toward this reaction when catalyzed by CYP3A4. Berberine inactivated CYP3A4 at a much faster rate than CYP3A5 and was a noncompetitive inhibitor of midazolam 4-hydroxylation by CYP3A4 but a strong mixed inhibitor of the CYP3A5 catalyzed reaction. These complex kinetics should be considered when extrapolating the risk for NP-drug interactions involving goldenseal. Robust kinetic parameters were determined for the reversible and timedependent inhibition of CYP2C9, CYP2D6, and CYP3A4/5 activities in human liver microsomes by major component isoquinoline alkaloids contained in the botanical natural product goldenseal. The alkaloid berberine also exhibited opposing, isoenzyme-specific allosteric effects on midazolam hydroxylation mediated by recombinant CYP3A4 (inhibition) and CYP3A5 (activation). These data will inform the development of a physiol. based pharmacokinetic model that can be used to predict potential clin. relevant goldenseal-drug interactions.

Drug Metabolism & Disposition published new progress about Alkaloids Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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

Wright, Kirsten M. published the artcileCentella asiatica water extract shows low potential for cytochrome P450-mediated drug interactions, Related Products of benzothiophene, the main research area is Centella asiatica water extract cytochromeP drug interaction.

Centella asiatica (CA) shows considerable promise for development as a botanical drug for cognitive decline. Its primary bioactive components include triterpene glycosides asiaticoside and madecassoside and their corresponding aglycons asiatic acid and madecassic acid. Exploration of the bioactivity of CA’s caffeoylquinic acids is ongoing. In this study, an aqueous extract of CA (CAW-R61J) was evaluated for drug interaction potential through inhibition or induction of P 450 enzymes, as required by the US Food and Drug Administration. CAW-R61J was assessed for induction potential of CYP1A2, CYP2B6, and CYP3A4 using transporter-certified cryopreserved human hepatocytes in sandwich culture. Gene expression of these target P450s was quantified, and enzyme activities were determined to confirm gene expression results. No induction was observed up to 16.7μg/mL CAW-R61J (equivalent to 1.1μM asiaticoside, 0.8μM madecassoside, 0.09μM asiatic acid, and 0.12μM madecassic acid). Reversible and time-dependent inhibitory effects of CAW-R61J on CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 were evaluated using human liver microsomes. CAW-R61J showed weak reversible inhibition of most of the P 450 forms tested, with the strongest being CYP2C9 (IC50 of 330μg/mL). CAW-R61J (â‰?000μg/mL) was not a time-dependent inhibitor of any of these P 450 enzymes. In summary, CAW-R61J had no, or only a weak impact, on P 450 induction and inhibition in vitro. The clin. relevance of these results will depend on the in vivo concentration of CAW-R61J components achieved in humans. Plasma triterpene concentrations measured in our recent clin. studies suggest minimal risk of P 450-mediated drug interactions by these components.

Drug Metabolism & Disposition published new progress about Aglycons Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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

Satoh, Daisuke published the artcileEstablishment of a novel hepatocyte model that expresses four cytochrome P450 genes stably via mammalian-derived artificial chromosome for pharmacokinetics and toxicity studies, SDS of cas: 40180-04-9, the main research area is hepatocyte cytochrome P450 artificial chromosome pharmacokinetics toxicity.

The utility of HepG2 cells to assess drug metabolism and toxicity induced by chem. compounds is hampered by their low cytochrome P 450 (CYP) activities. To overcome this limitation, we established HepG2 cell lines expressing major CYP enzymes involved in drug metabolism (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and CYP oxidoreductase (POR) using the mammalian-derived artificial chromosome vector. Transchromosomic HepG2 (TC-HepG2) cells expressing four CYPs and POR were used to determine time- and concentration-dependent inhibition and toxicity of several compounds by luminescence detection of CYP-specific substrates and cell viability assays. Gene expression levels of all four CYPs and POR, as well as the CYP activities, were higher in TC-HepG2 clones than in parental HepG2 cells. Addnl., the activity levels of all CYPs were reduced in a concentration-dependent manner by specific CYP inhibitors. Furthermore, preincubation of TC-HepG2 cells with CYP inhibitors known as time-dependent inhibitors (TDI) prior to the addition of CYP-specific substrates determined that CYP inhibition was enhanced in the TDI group than in the non-TDI group. Finally, the IC50 of bioactivable compound aflatoxin B1 was lower in TC-HepG2 cells than in HepG2 cells. In conclusion, the TC-HepG2 cells characterized in the current study are a highly versatile model to evaluate drug-drug interactions and hepatotoxicity in initial screening of candidate drug compounds, which require a high degree of processing capacity and reliability.

PLoS One published new progress about Albumins Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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

Sharma, Ashok K. published the artcileToxiM: a toxicity prediction tool for small molecules developed using machine learning and chemoinformatics approaches, Formula: C13H8Cl2O4S, the main research area is hepatotoxicity ToxiM machine learning chemoinformatics asbestos ethylene glycol; chemoinformatics; classification models; machine leaning; permeability; regression model; solubility; toxicity prediction.

The exptl. methods for the prediction of mol. toxicity are tedious and time-consuming tasks. Thus, the computational approaches could be used to develop alternative methods for toxicity prediction. We have developed a tool for the prediction of mol. toxicity along with the aqueous solubility and permeability of any mol./metabolite. Using a comprehensive and curated set of toxin mols. as a training set, the different chem. and structural based features such as descriptors and fingerprints were exploited for feature selection, optimization and development of machine learning based classification and regression models. The compositional differences in the distribution of atoms were apparent between toxins and non-toxins, and hence, the mol. features were used for the classification and regression. On 10-fold cross-validation, the descriptor-based, fingerprint-based and hybrid-based classification models showed similar accuracy (93%) and Matthews’s correlation coefficient (0.84). The performances of all the three models were comparable (Matthews’s correlation coefficient = 0.84-0.87) on the blind dataset. In addition, the regression-based models using descriptors as input features were also compared and evaluated on the blind dataset. Random forest based regression model for the prediction of solubility performed better (R2 = 0.84) than the multi-linear regression (MLR) and partial least square regression (PLSR) models, whereas, the partial least squares based regression model for the prediction of permeability (caco-2) performed better (R2 = 0.68) in comparison to the random forest and MLR based regression models. The performance of final classification and regression models was evaluated using the two validation datasets including the known toxins and commonly used constituents of health products, which attests to its accuracy. The ToxiM web server would be a highly useful and reliable tool for the prediction of toxicity, solubility, and permeability of small mols.

Frontiers in Pharmacology published new progress about Asbestos Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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

Hosaka, Shuto published the artcileBiomimetic trapping cocktail to screen reactive metabolites: use of an amino acid and DNA motif mixture as light/heavy isotope pairs differing in mass shift, Quality Control of 40180-04-9, the main research area is biomimetic trapping cocktail metabolite mass spectrometry drug screening; Activated drug; Cocktail reagent; Mass spectrometry; Trapping reagent.

Candidate drugs that can be metabolically transformed into reactive electrophilic products, such as epoxides, quinones, and nitroso compounds, are of special concern because subsequent covalent binding to bio-macromols. can cause adverse drug reactions, such as allergic reactions, hepatotoxicity, and genotoxicity. Several strategies have been reported for screening reactive metabolites, such as a covalent binding assay with radioisotope-labeled drugs and a trapping method followed by LC-MS/MS analyses. Of these, a trapping method using glutathione is the most common, especially at the early stage of drug development. However, the cysteine of glutathione is not the only nucleophilic site in vivo; lysine, histidine, arginine, and DNA bases are also nucleophilic. Indeed, the glutathione trapping method tends to overlook several types of reactive metabolites, such as aldehydes, acylglucuronides, and nitroso compounds Here, we introduce an alternate way for screening reactive metabolites as follows: A mixture of the light and heavy isotopes of simplified amino acid motifs and a DNA motif is used as a biomimetic trapping cocktail. This mixture consists of [2H0]/[2H3]-1-methylguanidine (arginine motif, Δ 3 Da), [2H0]/[2H4]-2-mercaptoethanol (cysteine motif, Δ 4 Da), [2H0]/[2H5]-4-methylimidazole (histidine motif, Δ 5 Da), [2H0]/[2H9]-n-butylamine (lysine motif, Δ 9 Da), and [13C0,15N0]/[13C1,15N2]-2′-deoxyguanosine (DNA motif, Δ 3 Da). Mass tag triggered data-dependent acquisition is used to find the characteristic doublet peaks, followed by specific identification of the light isotope peak using MS/MS. Forty-two model drugs were examined using an in vitro microsome experiment to validate the strategy. [Figure not available: see fulltext.].

Analytical and Bioanalytical Chemistry published new progress about DNA Role: ARG (Analytical Reagent Use), ANST (Analytical Study), USES (Uses). 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

Pumford, Neil R. published the artcileProtein targets of xenobiotic reactive intermediates, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is protein target xenobiotic reactive intermediate review.

A review and discussion with 168 references Many xenobiotics are metabolically activated to electrophilic intermediates that form covalent adducts with proteins; the mechanism of toxicity is either intrinsic or idiosyncratic in nature. Many intrinsic toxins covalently modify cellular proteins and somehow initiate a sequence of events that leads to toxicity. Major protein adducts of several intrinsic toxins have been identified and demonstrate significant decrease in enzymic activity. The reactivity of intermediates and subcellular localization of major targets maybe important in the toxicity. Major protein adducts of several intrinsic toxins have been identified and demonstrate significant decreases in enzymic activity. The reactivity of intermediates and subcellular localization of major targets may be important in the toxicity. Idiosyncratic toxicities are mediated through either a metabolic or immune-mediated mechanism. Xenobiotics that cause hypersensitivity/autoimmunity appear to have a limited number of protein targets, which are localized within the subcellular fraction where the electrophile is produced, are highly substituted, and are accessible to the immune system. Metabolic idiosyncratic toxins appear to have limited targets and are localized within a specific subcellular fraction. Identification of protein targets has given us insights into mechanisms of xenobiotic toxicity.

Annual Review of Pharmacology and Toxicology published new progress about Proteins Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Rao, Ponugoti published the artcileEffects of novel ethacrynic acid derivatives on human trabecular meshwork cell shape, actin cytoskeletal organization, and transcellular fluid flow, COA of Formula: C13H8Cl2O4S, the main research area is ethacrynic acid derivative trabecular meshwork actin cytoskeleton transcellular fluid.

To determine efficacy and therapeutic index in the context of ocular hypotensive activity of the new ethacrynic acid (ECA) derivatives of the 8000 series (SA8248 and SA8389), 9000 series (SA9000, SA9622 and SA9995) and ticrynafen, we undertook a comparative evaluation of the dose-dependent effects of these compounds on human trabecular meshwork (HTM) cell shape, actin cytoskeletal organization, focal adhesions and transcellular fluid flow. Responses were either scored using an arbitrary scale of 1 – 5 or quantified. Compounds of the 9000 series (SA9995 >SA9000 >SA9622) were found to be 14- to 20-fold more potent than ECA, ticrynafen or analogs from the 8000 series (SA8389>SA8248) in terms of ability to induce cell shape alterations in HTM cells. Similarly, compounds of the 9000 series (SA9995 >SA9622 >SA9000) were found to be much stronger (2 to 20 fold) than ECA, ticrynafen or analogs of the 8000 series in terms of affecting decreases in actin stress fiber content in HTM cells. Analogs of the 9000 series (SA9622 >SA9995 >SA9000) were also observed to be 8 to 10 fold more potent than ECA (SA8389 >ECA >SA8248 >ticrynafen) at eliciting decreases in cellular focal adhesions. Interestingly, analogs of the 9000 series (SA9000>SA9622>SA9995) and SA8248 demonstrated a huge increase (by many folds) in transcellular fluid flow of HTM cell monolayers as compared to ECA and ticrynafen. Collectively, these analyses revealed that the structural modification of ECA improves its ocular hypotensive efficacy, indicating that the SA9000 series compounds might be promising novel ocular hypotensive drugs.

Biological & Pharmaceutical Bulletin published new progress about Actins Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 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, COA of Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem