Category: 40180-04-9

Coen, Muireann published the artcileComparative NMR-based metabonomic investigation of the metabolic phenotype associated with tienilic acid and tienilic acid isomer, COA of Formula: C13H8Cl2O4S, the main research area is NMR metabonomic investigation metabolic phenotype tienilate isomer.

An NMR-based metabonomic approach was applied to study the systems level metabolic effects of two closely related thiophene compounds, tienilic acid (TA) and tienilic acid isomer (TAI). The metabonomic data were anchored with traditional clin. chem. and histopathol. analyses. TA was removed from the market as a result of suspected immune-mediated hepatotoxicity, whereas TAI is an intrinsic hepatotoxin. Equimolar doses of TA and TAI were administered to Sprague-Dawley rats, and sampling was conducted at 2, 6, and 24 h post-treatment. Histopathol. analyses revealed development of a significant hepatic lesion 24 h post-TAI treatment with a parallel increase in plasma alanine aminotransferase (ALT) activity. In contrast, TA was not associated with the development of a hepatic lesion or an increase in plasma ALT activity. High-resolution NMR spectral metabolic profiles were generated for liver extracts, plasma, and urine at multiple time points. Multivariate statistical tools were applied to model the metabolic profiles and identify discriminatory metabolites that reflected both the adaptation to TA administration and the onset and progression of TAI-induced hepatotoxicity. TAI was shown to induce marked metabolic effects on the metabolome at all time points, with dramatic metabolic perturbations at 24 h post-treatment correlating with the histopathol. and clin. chem. evidence of a hepatic lesion. The TAI-induced metabolic perturbations provided evidence for the generation of electrophilic reactive metabolites and a significant impairment of bioenergetic metabolic pathways. TA induced early metabolic perturbations that were largely resolved by 24 h post-treatment, suggesting the reestablishment of metabolic homeostasis and the ability to adapt to the intervention, with hepatic hypotaurine potentially representing a means of assessment of hepatic adaptation. This comparative metabonomic approach enabled the discrimination of metabolic perturbations that were common to both treatments and were interpreted as nontoxic thiophene-induced perturbations. Importantly, this approach enabled the identification of temporal metabolic perturbations that were unique to TAI or TA treatment and hence were of relevance to the development of toxicity or the ability to adapt. This approach is applicable to the future study of pharmacol. and structurally similar compounds and represents a refined means of identification of biomarkers of toxicity.

Chemical Research in Toxicology published new progress about Adaptation, animal. 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

Iwamura, Atsushi published the artcileCYP2C9-mediated metabolic activation of losartan detected by a highly sensitive cell-based screening assay, Application In Synthesis of 40180-04-9, the main research area is cytochrome CYP2C9 drug metabolism losartan hepatotoxicity adenovirus vector bioassay.

Drug-induced hepatotoxicity is a major problem in drug development, and reactive metabolites generated by cytochrome P 450s are suggested to be one of the causes. CYP2C9 is one of the major enzymes in hepatic drug metabolism In the present study, we developed a highly sensitive cell-based screening system for CYP2C9-mediated metabolic activation using an adenovirus vector expressing CYP2C9 (AdCYP2C9). Human hepatocarcinoma HepG2 cells infected with our constructed AdCYP2C9 for 2 days at multiplicity of infection 10 showed significantly higher diclofenac 4′-hydroxylase activity than human hepatocytes. AdCYP2C9-infected cells were treated with several hepatotoxic drugs, resulting in a significant increase in cytotoxicity by treatment with losartan, benzbromarone, and tienilic acid. Metabolic activation of losartan by CYP2C9 has never been reported, although the metabolic activations of benzbromarone and tienilic acid have been reported. To identify the reactive metabolites of losartan, the semicarbazide adducts of losartan were investigated by liquid chromatog.-tandem mass spectrometry. Two CYP2C9-specific semicarbazide adducts of losartan (S1 and S2) were detected. S2 adduct formation suggested that a reactive metabolite was produced from the aldehyde metabolite E3179, but a possible metabolite from S1 adduct formation was not produced via E3179. In conclusion, a highly sensitive cell-based assay to evaluate CYP2C9-mediated metabolic activation was established, and we found for the first time that CYP2C9 is involved in the metabolic activation of losartan. This cell-based assay system would be useful for evaluating drug-induced cytotoxicity caused by human CYP2C9.

Drug Metabolism and Disposition published new progress about Adenoviral vectors. 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

Gerets, Helga H. J. published the artcileInvestigation of the Nrf2 Stress Response at Cellular Level to Detect Compounds Inducing Oxidative and Electrophilic Stress, Formula: C13H8Cl2O4S, the main research area is Nrf2 oxidative electrophilic stress liver injury.

Drug-induced liver injury (DILI) remains a significant reason for drug attrition and withdrawal. DILI can be caused by several mechanisms, one of these is the formation of reactive metabolites (RM) leading to oxidative and electrophilic stress. Since such event activates NF-E2-related factor-2 (Nrf2) and its downstream pathways, it seems relevant to measure Nrf2 activation. In this article, Nrf2 activation was evaluated using two approaches. First, three human hepatocytes donors and HepG2 cells were exposed to five compounds known to produce RM- and four non-RM forming compounds The expression of seven genes under the regulation of Nrf2 was measured. An index was calculated taking into account the results of the seven genes. Subsequently, the mean index for the RM-forming and the non-RM-forming compounds was calculated for each donor, and the midpoint between these two values was determined, which represents the donor-specific threshold and the compounds were classified accordingly. All three donors obtained a sensitivity of 80% (4/5) and a specificity between 75% (3/4) and 100% (4/4). HepG2 cells obtained 80% (4/5) sensitivity, but very poor specificity 0% (0/4), which makes them less suitable, compared to human hepatocytes donors, for screening of electrophilic stress. Second, the Antioxidant-Response-Element-Reporter-Cell Line, AREc32, was exposed to the same set of compounds in addition to 13 RM-forming and 5 non-RM-forming compounds Using an arbitrary cutoff of 1.5, a sensitivity of 78% (14/18) and a specificity of 88% (7/8) were obtained. Acceptable predictive values and easiness of use make the AREC32 assay more suited to investigate Nrf2 activation compared to the first approach.

Applied In Vitro Toxicology published new progress about Cell line (AREc32). 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

Hosey, Chelsea M. published the artcileBDDCS Predictions, Self-Correcting Aspects of BDDCS Assignments, BDDCS Assignment Corrections, and Classification for more than 175 Additional Drugs, Application In Synthesis of 40180-04-9, the main research area is afatinib alclofenac alpidem amifloxacin pharmacogenomics drug interaction toxicity; BDDCS; biopharmaceutics drug disposition classification system; disposition; drug development; drug transport.

The biopharmaceutics drug disposition classification system was developed in 2005 by Wu and Benet as a tool to predict metabolizing enzyme and drug transporter effects on drug disposition. The system was modified from the biopharmaceutics classification system and classifies drugs according to their extent of metabolism and their water solubility By 2010, Benet et al. had classified over 900 drugs. In this paper, we incorporate more than 175 drugs into the system and amend the classification of 13 drugs. We discuss current and addnl. applications of BDDCS, which include predicting drug-drug and endogenous substrate interactions, pharmacogenomic effects, food effects, elimination routes, central nervous system exposure, toxicity, and environmental impacts of drugs. When predictions and classes are not aligned, the system detects an error and is able to self-correct, generally indicating a problem with initial class assignment and/or measurements determining such assignments.

AAPS Journal published new progress about Biological permeation. 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

Pacitto, Stephanie R. published the artcileChanges in gene expression induced by tienilic acid and sulfamethoxazole: testing the danger hypothesis, HPLC of Formula: 40180-04-9, the main research area is tienilic acid sulfamethoxazole gene expression microarray idiosyncratic drug toxicity; cell stress tienilate sulfamethoxazole idiosyncratic drug toxicity.

Tienilic acid (TA) was withdrawn due to idiosyncratic hepatotoxicity. Two hypotheses for the mechanisms of idiosyncratic reactions are the hapten and danger hypotheses, which are not mutually exclusive. Both human CYP 2C9 and rat CYP 2C11 metabolize TA to a reactive metabolite that was reported to bind exclusively to these enzymes. TA-Induced liver toxicity is associated with antibodies against CYP 2C9, thus TA appears to act as a hapten. However, if the binding were limited to CYP 2C, it is unlikely that this would lead to significant cell stress. If TA does not cause cell stress it would suggest that acting as a hapten is sufficient to induce an idiosyncratic reaction. To test whether TA can cause cell stress rats were dosed with TA and hepatic gene expression was profiled at 6 and 24 h after drug administration. TA induced changes in genes involved in oxidative stress (aldo-keto reductase, glutathione-S-transferase, thioredoxin reductase, epoxide hydrolase), inflammation (IL-1β, interferon regulatory factor 1, macrophage stimulating protein 1), cytotoxicity (caspase-12), and liver regeneration (p27Kip1, DUSP6, serine dehydratase, spectrin βII, inhibin βA). These data support the hypothesis that danger signals in the form of cell-stress may be involved in initiating the immune response observed in TA-induced toxicity. In sep. experiments, the authors examined the changes in gene expression induced in mice by sulfamethoxazole, which also causes idiosyncratic reactions. Sulfamethoxazole is an aromatic amine, and aromatic amines in general are associated with idiosyncratic drug reactions. They form reactive metabolites that both act as electrophiles and can redox cycle; therefore, it was assumed that sulfamethoxazole would cause some type of cell stress, the only question was what changes in mRNA expression would occur. In contrast to expectations, no changes induced by sulfamethoxazole could easily be interpreted as a danger signal. These data are presented together because they are the opposite of the expected results and convey a complex story.

Journal of Immunotoxicology published new progress about Antibacterial agents. 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, HPLC of Formula: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Murcia-Soler, Miguel published the artcileDiscrimination and selection of new potential antibacterial compounds using simple topological descriptors, Product Details of C13H8Cl2O4S, the main research area is antibacterial topol structure activity relationship.

The aim of the work was to discriminate between antibacterial and non-antibacterial drugs by topol. methods and to select new potential antibacterial agents from among new structures. The method used for antibacterial activity selection was a linear discriminant anal. (LDA). It is possible to obtain a QSAR interpretation of the information contained in the discriminant function. We make use of the pharmacol. distribution diagrams (PDDs) as a visualizing technique for the identification and selection of new antibacterial agents.

Journal of Molecular Graphics & Modelling published new progress about Antibacterial agents. 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

Vicente-Carrillo, A. published the artcileBoar spermatozoa successfully predict mitochondrial modes of toxicity: Implications for drug toxicity testing and the 3R principles, Related Products of benzothiophene, the main research area is boar sperm mitochondria toxicity drug testing; Boar; Drug; Mitochondria; Motility; Sperm; Toxicity.

Replacement of animal testing by in vitro methods (3-R principles) requires validation of suitable cell models, preferably obtained non-invasively, defying traditional use of explants. Ejaculated spermatozoa are highly dependent on mitochondrial production and consumption of ATP for their metabolism, including motility display, thus becoming a suitable model for capturing multiple modes of action of drugs and other chems. acting via mitochondrial disturbance. In this study, a hypothesis was tested that the boar spermatozoon is a suitable cell type for toxicity assessment, providing a protocol for 3R-replacement of animals for research and drug-testing. Boar sperm kinetics was challenged with a wide variety of known frank mito-toxic chems. with previously shown mitochondrial effects, using a semi-automated motility analyzer allied with real-time fluorescent probing of mitochondrial potential (MitoTracker & JC-1). Output of this sperm assay (obtained after 30 min) was compared to cell viability (ATP-content, data obtained after 24-48 h) of a hepatome-cell line (HepG2). Results of compound effects significantly correlated for all sperm variables and for most variables in (HepG2). Dose-dependent decreases of relative ATP content in HepG2 cells correlated to sperm speed (r = 0.559) and proportions of motile (r = 0.55) or progressively motile (r = 0.53) spermatozoa. The significance of the study relies on the objectivity of computerized testing of sperm motility inhibition which is comparable albeit of faster output than somatic cell culture models. Sperm suspensions, easily and painlessly obtained from breeding boars, are confirmed as suitable biosensors for preclin. toxicol. screening and ranking of lead compounds in the drug development processes.

Toxicology In Vitro published new progress about Antimicrobial agents. 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

Lecoeur, S. published the artcileTienilic acid-induced autoimmune hepatitis: anti-liver and -kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9, Recommanded Product: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is autoimmune hepatitis tienilic acid cytochrome P4502C9.

Tienilic acid-induced hepatitis is characterized by the presence of anti-liver and -kidney microsomal (anti-LKM2) autoantibodies in patient sera. Cytochrome P 4502C9 (CYP2C9), involved in the metabolism of tienilic acid, was shown to be a target for tienilic acid-reactive metabolites and for autoantibodies. To further investigate the relationship between drug metabolism and the pathogenesis of this drug-induced autoimmune disease, the specificity of anti-LKM2 autoantibodies toward CYP2C9 was first determined, and the antigen sites on CYP2C9 were localized. By constructing several deletion mutants derived from CYP2C9 cDNA and by probing the corresponding proteins with different anti-LKM2 sera, we defined three regions (amino acids 314-322, 345-356, and 439-455); they interacted to form a major conformational autoantibody binding site. This binding site was immunoreactive with 100% of sera and allowed removal of the entire reactivity of the sera tested by immunoblotting. Epitope mapping studies have been performed for CYP2D6, CYP17, CYP21A2, and, recently, CYP3A. Those data were compared with the results obtained in the current study with CYP2C9 in an attempt to elucidate one of the mechanisms by which CYP becomes immunogenic.

Molecular Pharmacology published new progress about Autoimmune hepatitis. 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

Dansette, P. M. published the artcileDrug-induced immunotoxicity, Application In Synthesis of 40180-04-9, the main research area is review drug immunotoxicity liver.

A review with 70 references is given on immune-response-related drug hepatitis. A number of organs may be the target of such reactions; however, this review concentrates mostly on the liver. Drug-induced hepatitis is generally divided into 2 categories: acute hepatitis in which the drug or a metabolite destroys a vital target in the cell; immunoallergic hepatitis in which the drug triggers an adverse immune response directed against the liver. Their clin. features are: (a) low frequency; (b) dose independence; (c) typical immune system manifestations such as fever, eosinophilia; (d) delay between the initiation of treatment and onset of the disease; (e) a shortened delay upon rechallenge; and (f) occasional presence of autoantibodies in the blood serum of patients. Such signs were found in cases of hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine, and anticonvulsants. They will be taken as examples to demonstrate the recent progress made in determining the mechanisms responsible for the disease. The following mechanisms were postulated. (1) The drug is 1st metabolized into a reactive metabolite which binds to the enzyme that generated it. (2) This produces a neo-antigen which, once presented to the immune system, might trigger an immune response characterized by (3) the production of antibodies recognizing both the native and/or the modified protein. (4) Rechallenge leads to increased neoantigen production, a situation in which the presence of antibodies may induce cytolysis. Toxicity is related to the nature and amount of neoantigen and also to other factors such as the individual immune system. An effort should be made to better understand the precise mechanisms underlying this kind of disease and thereby identify the drugs at risk; and also the neoantigen processes necessary for their introduction into the immune system. An animal model would be useful in this regard.

European Journal of Drug Metabolism and Pharmacokinetics published new progress about Autoimmune hepatitis. 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

Lopez-Garcia, M. Pilar published the artcileKinetics of tienilic acid bioactivation and functional generation of drug-protein adducts in intact rat hepatocytes, Category: benzothiophene, the main research area is tienilic acid bioactivation protein adduct hepatocyte.

Drug-induced autoimmune hepatitis is among the most severe hepatic idiosyncratic adverse drug reactions. Considered multifactorial, the disease combines immunol. and metabolic aspects, the latter being to date much better known. As for many other model drugs, studies on tienilic acid (TA)-induced hepatitis have evidenced the existence of bioactivation during the hepatic oxidation of the drug, allowing the identification of the neoantigen of anti-LKM2 autoantibodies and the pathway responsible for its formation. However, most of these results are based on the use of microsomal fractions whose relevance to the liver in vivo still needs to be established. In the more complex intact cell environment, several endogenous processes may play a significant role on triggering the reaction and should therefore be considered. In this work the authors have characterized the kinetics of TA biotransformation in metabolically competent hepatocytes, the influence of TA bioactivation on physiol. GSH levels, and the qual. and quant. profile of drug-protein conjugates generated in situ, as a function of exposure time. Results confirm that intact hepatocytes reproduce in vitro the metabolic sequence that leads to the functional generation of drug-protein adducts, in conditions that simulate clin. human exposure to TA. Metabolically competent cultured hepatocytes appear as a very promising approach to investigate the early preimmunol. events of drug-induced autoimmune hepatitis, adequate to identify the conditions that may modulate the formation and specificity of drug-protein adducts in vivo, to study the hepatic disposition of the TA-protein targets, and to define the specific role of the hepatocyte in the origin of this adverse reaction.

Biochemical Pharmacology published new progress about Autoimmune hepatitis. 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